Negative allosteric modulators of metabotropic glutamate receptor 2

ABSTRACT

Described are negative allosteric modulators of metabotropic glutamate receptor 2 (mGlu 2 ), pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for treating depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer&#39;s disease, or autism spectrum disorders in a subject.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a non-provisional of and claims priority to U.S.Provisional Application No. 62/107,821, filed Jan. 26, 2015, the entirecontent of which is incorporated herein by reference.

STATEMENT OF GOVERNMENT INTEREST

This invention was made with government support under Grant number 5 U54MH84659-06 awarded by the National Institute of Mental Health (NIMH).The government has certain rights in the invention.

TECHNICAL FIELD

The present disclosure relates to compounds, compositions, and methodsfor treating metabotropic glutamate receptor 2 related diseases and/ordisorders, such as depression, anxiety, obsessive-compulsive disorder,cognitive disorders, Alzheimer's disease, and autism spectrum disorders.

BACKGROUND

Metabotropic glutamate (mGlu) receptors, a class of G-protein coupledreceptor (GPCR) family C, have recently emerged as targets of potentialtherapeutic value. They bind glutamate, an amino acid that is the mostprominent excitatory neurotransmitter in the human central nervoussystem (CNS). mGlus are known to activate biochemical cascades, leadingto the modification of other proteins. For example, this can lead tochanges in a synapse's excitability by presynaptic inhibition ofneurotransmission, or modulation and even induction of postsynapticresponses.

Metabotropic glutamate receptor 2 (mGlu₂) is one of eight mGlus thathave been identified, and, along with mGlu₃, is classified as a group IImGlu. Group II mGlus play an important role is synaptic plasticity,which directly effects cognitive function (including learning andmemory), among other things. The effects of group II mGlus occurprimarily presynaptically via their inhibition of glutamate release.These effects can also be due to the inhibition of non-vesicularglutamate release from glia. However, group II receptors are known toalso reduce the activity of postsynaptic potentials, both excitatory andinhibitory, in the cortex.

Dysfunction of mGlu₂ has been implicated in many diseases and/ordisorders. Hence, targeting mGlu₂ activity has been the subject of muchinvestigation. Several reports have highlighted its link to a variety ofdiseases, such as depression, anxiety, obsessive-compulsive disorder,cognitive disorders, Alzheimer's disease, and autism spectrum disorders.Accordingly, there exists a need for selective modulators of mGlu₂.

SUMMARY OF THE INVENTION

In one aspect, disclosed are compounds of formula (I),

or a pharmaceutically acceptable salt thereof, wherein

R¹ is aryl, heteroaryl, heterocycle, or cycloalkyl;

R^(2a), R^(2b), and R^(2c) are each independently selected fromhydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄haloalkoxy;

R³ is —X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A;

p is 0-2;

q is 0-2;

X, Y, and Z are each independently selected from a bond, CR^(8e)R^(8f),O, S, NR¹⁰, —C(O)—, —O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—,—NR¹⁰—C(O)—, —NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—;

R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,C₁-C₇ haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, orR^(7a) and R^(7b) together with the nitrogen atom to which they attachform a heterocycle;

R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;

R¹⁰ at each occurrence is independently selected from hydrogen, C₁-C₄alkyl, and C₁-C₄ haloalkyl;

A is aryl, heteroaryl, cycloalkyl, or heterocycle;

A′ is aryl, heteroaryl, cycloalkyl, or heterocycle; and

R⁴ is —CONH₂ or cyano;

wherein said aryl, heteroaryl, cycloalkyl, and heterocycle, at eachoccurrence, are independently substituted or unsubstituted.

Also disclosed are pharmaceutical compositions comprising the compounds,methods of making the compounds, and methods of using the compounds fortreatment of metabotropic glutamate receptor 2 related diseases and/ordisorders.

DETAILED DESCRIPTION

Disclosed herein are negative allosteric modulators (NAMs) of mGlu₂. Themodulators can have formula (I). Compounds of formula (I) may exhibitselectivity for mGlu₂ over other mGlu receptors. Compounds of formula(I) can be used to treat or prevent diseases and disorders associatedwith mGlu₂ by modulating mGlu₂ activity. mGlu₂ has been implicated in anumber of different diseases and disorders including, but not limitedto, depression, anxiety, obsessive-compulsive disorder, cognitivedisorders, Alzheimer's disease, and autism spectrum disorders.

Since the orthosteric binding sites of the mGlu isoforms are highlyconserved, very few selective modulators of the mGlus that bind at theorthosteric site have been identified. One strategy to selectively bindand modulate the mGlus includes identifying allosteric sites which maybe amenable to modulation by a small molecule. In particular, negativeallosteric modulation of mGlu₂ can result in inhibition of processesgoverned by mGlu₂ and provide therapeutic benefits for disorders causedby mGlu₂ dysfunction.

1. Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. In case of conflict, the present document, includingdefinitions, will control. Preferred methods and materials are describedbelow, although methods and materials similar or equivalent to thosedescribed herein can be used in practice or testing of the presentinvention. All publications, patent applications, patents and otherreferences mentioned herein are incorporated by reference in theirentirety.

The materials, methods, and examples disclosed herein are illustrativeonly and not intended to be limiting.

The terms “comprise(s),” “include(s),” “having,” “has,” “can,”“contain(s),” and variants thereof, as used herein, are intended to beopen-ended transitional phrases, terms, or words that do not precludethe possibility of additional acts or structures. The singular forms“a,” “an” and “the” include plural references unless the context clearlydictates otherwise. The present disclosure also contemplates otherembodiments “comprising,” “consisting of” and “consisting essentiallyof,” the embodiments or elements presented herein, whether explicitlyset forth or not.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (forexample, it includes at least the degree of error associated with themeasurement of the particular quantity). The modifier “about” shouldalso be considered as disclosing the range defined by the absolutevalues of the two endpoints. For example, the expression “from about 2to about 4” also discloses the range “from 2 to 4.” The term “about” mayrefer to plus or minus 10% of the indicated number. For example, “about10%” may indicate a range of 9% to 11%, and “about 1” may mean from0.9-1.1. Other meanings of “about” may be apparent from the context,such as rounding off, so, for example “about 1” may also mean from 0.5to 1.4.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this disclosure, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in Organic Chemistry, Thomas Sorrell, University ScienceBooks, Sausalito, 1999; Smith and March March's Advanced OrganicChemistry, 5^(th) Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., NewYork, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd)Edition, Cambridge University Press, Cambridge, 1987; the entirecontents of each of which are incorporated herein by reference. The term“alkoxy” as used herein, refers to an alkyl group, as defined herein,appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “loweralkyl” or “C₁-C₆-alkyl” means a straight or branched chain hydrocarboncontaining from 1 to 6 carbon atoms. The term “C₁-C₃-alkyl” means astraight or branched chain hydrocarbon containing from 1 to 3 carbonatoms. Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkoxyalkyl” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “alkylene”, as used herein, refers to a divalent group derivedfrom a straight or branched chain hydrocarbon of 1 to 10 carbon atoms,for example, of 2 to 5 carbon atoms. Representative examples of alkyleneinclude, but are not limited to, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,and —CH₂CH₂CH₂CH₂CH₂—.

The term “aryl” as used herein, refers to a phenyl group, or a bicyclicfused ring system. Bicyclic fused ring systems are exemplified by aphenyl group appended to the parent molecular moiety and fused to acycloalkyl group, as defined herein, a phenyl group, a heteroaryl group,as defined herein, or a heterocycle, as defined herein. Representativeexamples of aryl include, but are not limited to, indolyl, naphthyl,phenyl, quinolinyl and tetrahydroquinolinyl.

The term “cycloalkyl” as used herein, refers to a carbocyclic ringsystem containing three to ten carbon atoms, zero heteroatoms and zerodouble bonds. Representative examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

The term “cycloalkenyl” as used herein, means a non-aromatic monocyclicor multicyclic ring system containing at least one carbon-carbon doublebond and preferably having from 5-10 carbon atoms per ring. Exemplarymonocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl orcycloheptenyl.

The term “fluoroalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, seven or eighthydrogen atoms are replaced by fluorine. Representative examples offluoroalkyl include, but are not limited to, 2-fluoroethyl,2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,and trifluoropropyl such as 3,3,3-trifluoropropyl.

The term “alkoxyfluoroalkyl” as used herein, refers to an alkoxy group,as defined herein, appended to the parent molecular moiety through afluoroalkyl group, as defined herein.

The term “fluoroalkoxy” as used herein, means at least one fluoroalkylgroup, as defined herein, is appended to the parent molecular moietythrough an oxygen atom. Representative examples of fluoroalkyloxyinclude, but are not limited to, difluoromethoxy, trifluoromethoxy and2,2,2-trifluoroethoxy.

The term “halogen” or “halo” as used herein, means Cl, Br, I, or F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, seven or eighthydrogen atoms are replaced by a halogen.

The term “haloalkoxy” as used herein, means at least one haloalkylgroup, as defined herein, is appended to the parent molecular moietythrough an oxygen atom.

The term “heteroalkyl” as used herein, means an alkyl group, as definedherein, in which one or more of the carbon atoms has been replaced by aheteroatom selected from S, O, P and N. Representative examples ofheteroalkyls include, but are not limited to, alkyl ethers, secondaryand tertiary alkyl amines, amides, and alkyl sulfides.

The term “heteroaryl” as used herein, refers to an aromatic monocyclicring or an aromatic bicyclic ring system. The aromatic monocyclic ringsare five or six membered rings containing at least one heteroatomindependently selected from the group consisting of N, O and S (e.g. 1,2, 3, or 4 heteroatoms independently selected from O, S, and N). Thefive membered aromatic monocyclic rings have two double bonds and thesix membered six membered aromatic monocyclic rings have three doublebonds. The bicyclic heteroaryl groups are exemplified by a monocyclicheteroaryl ring appended to the parent molecular moiety and fused to amonocyclic cycloalkyl group, as defined herein, a monocyclic aryl group,as defined herein, a monocyclic heteroaryl group, as defined herein, ora monocyclic heterocycle, as defined herein. Representative examples ofheteroaryl include, but are not limited to, indolyl, pyridinyl(including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl,thiazolyl, and quinolinyl.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic heterocycle, a bicyclic heterocycle, or a tricyclicheterocycle. The monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S. Thethree- or four-membered ring contains zero or one double bond, and oneheteroatom selected from the group consisting of O, N, and S. Thefive-membered ring contains zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. Thesix-membered ring contains zero, one or two double bonds and one, two,or three heteroatoms selected from the group consisting of O, N, and S.The seven- and eight-membered rings contains zero, one, two, or threedouble bonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle is a monocyclic heterocycle fused to a phenyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle, or a spiro heterocyclegroup, or a bridged monocyclic heterocycle ring system in which twonon-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2,3, or 4 carbon atoms, or an alkenylene bridge of two, three, or fourcarbon atoms. Representative examples of bicyclic heterocycles include,but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydroisoquinoline, 2-azaspiro[3.3]heptan-2-yl,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non-adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but are not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). The monocyclic, bicyclic, andtricyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl or cycloalkyl) is indicated by the prefix“C_(x)-C_(y)-”, wherein x is the minimum and y is the maximum number ofcarbon atoms in the substituent. Thus, for example, “C₁-C₃-alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.

The term “substituents” refers to a group “substituted” on an aryl,heteroaryl, phenyl or pyridinyl group at any atom of that group. Anyatom can be substituted.

The term “substituted” refers to a group that may be further substitutedwith one or more non-hydrogen substituent groups. Substituent groupsinclude, but are not limited to, halogen, ═O, ═S, cyano, nitro,fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl,haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy,benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl,aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, and acyl.

For compounds described herein, groups and substituents thereof may beselected in accordance with permitted valence of the atoms and thesubstituents, such that the selections and substitutions result in astable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

For the recitation of numeric ranges herein, each intervening numberthere between with the same degree of precision is explicitlycontemplated. For example, for the range of 6-9, the numbers 7 and 8 arecontemplated in addition to 6 and 9, and for the range 6.0-7.0, thenumber 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 areexplicitly contemplated.

2. Compounds

In one aspect, disclosed is a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is aryl,heteroaryl, heterocycle, or cycloalkyl; R^(2a), R^(2b), and R^(2c) areeach independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) and R^(7b)are each independently selected from C₁-C₇ alkyl, C₁-C₇ haloalkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂ or cyano;wherein said aryl, heteroaryl, cycloalkyl, and heterocycle, at eachoccurrence, are independently substituted or unsubstituted.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each independently selectedfrom hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, andC₁-C₄ haloalkoxy; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) and R^(7b)are each independently selected from C₁-C₇ alkyl, C₁-C₇ haloalkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂ or cyano;wherein said aryl, heteroaryl, cycloalkyl, and heterocycle, at eachoccurrence, are each independently unsubstituted or substituted with 1,2, 3, 4, 5, 6, or 7 functional groups independently selected from thegroup consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl,alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl,haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy,benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl,aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, and acyl.

In certain embodiments, R¹ is aryl or heteroaryl.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl. In certain embodiments, R¹ isheteroaryl substituted with 0-1 substituents selected from C₁-C₃ alkyl.In certain embodiments, R¹ is isothiazolyl substituted with 0-1substituents selected from C₁-C₃ alkyl.

In certain embodiments, R¹ is phenyl substituted with 0-2 substituentsindependently selected from fluoro and methoxy.

In certain embodiments, R¹ is phenyl. In certain embodiments, R¹ ispyridyl. In certain embodiments, R¹ is isothiazolyl. In certainembodiments, R¹ is thiazolyl. In certain embodiments, R¹ is pyrazolyl.In certain embodiments, R¹ is imidazolyl. In certain embodiments, R¹ ispyrrolyl. In certain embodiments, R¹ is thienyl. In certain embodiments,R¹ is furanyl. In certain embodiments, R¹ is benzofuranyl. In certainembodiments, R¹ is benzothienyl. In certain embodiments, R¹ is indolyl.In certain embodiments, R¹ is naphthyl. In certain embodiments, R¹ isquinolinyl. In certain embodiments, R¹ is tetrahydroquinolinyl. Incertain embodiments, R¹ is pyrimidinyl. In certain embodiments, R¹ ispyridazinyl. In certain embodiments, R¹ is pyrazinyl. In certainembodiments, R¹ is oxazolyl. In certain embodiments, R¹ is isoxazolyl.

In certain embodiments, R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro. In certain embodiments,R^(2a), R^(2b), and R^(2c) are each hydrogen. In certain embodiments,R^(2a) and R^(2b) are hydrogen, and R^(2c) is fluoro. In certainembodiments, R^(2a) is hydrogen, and R^(2b) and R^(2c) are eachindependently hydrogen or fluoro.

In certain embodiments, R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl or heterocycle; and A′ is aryl,heteroaryl, cycloalkyl, or heterocycle.

In certain embodiments, R³ is—X—(CR^(8a)R^(8b))_(p)(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)) or—X—(CR^(8a)R^(8b))_(p)(CR^(8c)R^(8d))_(q)—Y-A; wherein p is 0-2; q is0-2; X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f),O, or NR¹⁰; R^(7a) and R^(7b) are each independently selected from C₁-C₇alkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; and A is aryl, heteroaryl, cycloalkyl or heterocycle.

In certain embodiments, R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms.

In certain embodiments, R³ is

wherein X, Y, R^(7a), R^(7b), R^(8a), R^(8b), R^(8c), R^(8d), R⁹, m andA are as defined in any of the previous embodiments.

In certain embodiments, R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms.

In certain embodiments, R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)), providedthat when q=0, Z is not O, S, NR¹⁰, —C(O)—O—, —O—C(O)—NR¹⁰—,—C(O)—NR¹⁰—, —NR¹⁰—C(O)—O—, or —NR¹⁰—C(O)—NR¹⁰—.

In certain embodiments, R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)), providedthat when p=0, then Z and X do not form an O—O, N—N, O—N, or N—O bond.

In certain embodiments, R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A, provided that whenq=0, Z and Y do not form an O—O, N—N, O—N, or N—O bond.

In certain embodiments, R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A, provided that whenp=0, Z and X do not form an O—O, N—N, O—N, or N—O bond.

In certain embodiments, R³ is-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), provided that when p=0, Xis not O, S, NR¹⁰, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—O—,or —NR¹⁰—C(O)—NR¹⁰—.

In certain embodiments, R³ is -A′—X—(CR^(8a)R^(8b))_(p)—Y-A, providedthat when p=0, X and Y do not form an O—O, N—N, O—N, or N—O bond.

In certain embodiments, A′ is aryl, heteroaryl, cycloalkyl, orheterocycle. In certain embodiments, A′ is cycloalkyl or heterocycle.

In certain embodiments, A′ is a monocyclic heteroaryl. In certainembodiments, A′ is a monocyclic heterocycle. In certain embodiments, A′is bicyclic heterocycle. In certain embodiments, A′ is a monocyclicheterocycle fused to a phenyl group. In certain embodiments, A′ is amonocyclic heterocycle fused to a monocyclic cycloalkenyl. In certainembodiments, A′ is a monocyclic heterocycle fused to a monocyclicheterocycle. In certain embodiments, A′ is a spiro heterocycle. Incertain embodiments, A′ is a bridged monocyclic heterocycle ring system.In certain embodiments, A′ is a tricyclic heterocycle. In certainembodiments, A′ is a bicyclic heterocycle fused to a phenyl group. Incertain embodiments, A′ is a bicyclic heterocycle fused to a monocycliccycloalkyl. In certain embodiments, A′ is a bicyclic heterocycle fusedto a monocyclic cycloalkenyl. In certain embodiments, A′ is a bicyclicheterocycle fused to a monocyclic heterocycle. In certain embodiments,A′ is a bicyclic heterocycle in which two non-adjacent atoms of thebicyclic ring are linked by an alkylene bridge. In certain embodiments,A′ is an aromatic monocyclic ring. In certain embodiments, A′ is anaromatic bicyclic ring system. In certain embodiments, A′ is acycloalkyl. In certain embodiments, A′ is unsubstituted. In certainembodiments, A′ is substituted with 1, 2, 3, 4, 5, 6, or 7 functionalgroups independently selected from the group consisting of halogen, ═O,═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl,alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl,heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino,aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl,alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone,amide, carbamate, and acyl.

In certain embodiments, A is a monocyclic heteroaryl. In certainembodiments, A is a monocyclic heterocycle. In certain embodiments, A isbicyclic heterocycle. In certain embodiments, A is a monocyclicheterocycle fused to a phenyl group. In certain embodiments, A is amonocyclic heterocycle fused to a monocyclic cycloalkenyl. In certainembodiments, A is a monocyclic heterocycle fused to a monocyclicheterocycle. In certain embodiments, A is a spiro heterocycle. Incertain embodiments, A is a bridged monocyclic heterocycle ring system.In certain embodiments, A is a tricyclic heterocycle. In certainembodiments, A is a bicyclic heterocycle fused to a phenyl group. Incertain embodiments, A is a bicyclic heterocycle fused to a monocycliccycloalkyl. In certain embodiments, A is a bicyclic heterocycle fused toa monocyclic cycloalkenyl. In certain embodiments, A is a bicyclicheterocycle fused to a monocyclic heterocycle. In certain embodiments, Ais a bicyclic heterocycle in which two non-adjacent atoms of thebicyclic ring are linked by an alkylene bridge. In certain embodiments,A is an aromatic monocyclic ring. In certain embodiments, A is anaromatic bicyclic ring system. In certain embodiments, A is acycloalkyl. In certain embodiments, A is unsubstituted. In certainembodiments, A is substituted with 1, 2, 3, 4, 5, 6, or 7 functionalgroups independently selected from the group consisting of halogen, ═O,═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl,alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl,heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino,aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl,alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone,amide, carbamate, and acyl.

In certain embodiments, R³ is a monocyclic heteroaryl. In certainembodiments, R³ is a monocyclic heterocycle. In certain embodiments, R³is bicyclic heterocycle. In certain embodiments, R³ is a monocyclicheterocycle fused to a phenyl group. In certain embodiments, R³ is amonocyclic heterocycle fused to a monocyclic cycloalkenyl. In certainembodiments, R³ is a monocyclic heterocycle fused to a monocyclicheterocycle. In certain embodiments, R³ is a spiro heterocycle. Incertain embodiments, R³ is a bridged monocyclic heterocycle ring system.In certain embodiments, R³ is a tricyclic heterocycle. In certainembodiments, R³ is a bicyclic heterocycle fused to a phenyl group. Incertain embodiments, R³ is a bicyclic heterocycle fused to a monocycliccycloalkyl. In certain embodiments, R³ is a bicyclic heterocycle fusedto a monocyclic cycloalkenyl. In certain embodiments, R³ is a bicyclicheterocycle fused to a monocyclic heterocycle. In certain embodiments,R³ is a bicyclic heterocycle in which two non-adjacent atoms of thebicyclic ring are linked by an alkylene bridge. In certain embodiments,R³ is an aromatic monocyclic ring. In certain embodiments, R³ is anaromatic bicyclic ring system. In certain embodiments, R³ isunsubstituted. In certain embodiments, R³ is substituted with 1-7functional groups independently selected from the group consisting ofhalogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl,fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy,heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle,cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino,alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl,—COOH, ketone, amide, carbamate, and acyl.

In certain embodiments, R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₃ alkyl and C₃-C₅ cycloalkyl, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are each independentlyselected from hydrogen and methyl; R⁹ at each occurrence isindependently selected from pyridyl and morpholinyl; wherein 0-1 R⁹groups are present in each R³; m is 0 -1; R¹⁰ is hydrogen or C₁-C₃alkyl; A is pyridyl, pyrimidinyl, morpholinyl, pyrrolidinyl,piperidinyl, pyrazolinyl, tetrahydropyranyl, piperazinyl,1,1-dioxothiomorpholinyl, 1, -dioxo-1,4-thiazepanyl, 1,4-diazepanyl,1,4-thiazepanyl, 1,4-oxazepanyl, azepanyl, 2-azaspiro[3.3]heptan-2-yl,decahydroquinolyl; wherein A is substituted with 0-2 substituentsindependently selected from fluoro, chloro, cyano, methyl, —CH₂CF₃,methoxy, SO₂Me, acyl, and cyclopropyl.

In certain embodiments, R⁴ is —CONH₂. In certain embodiments, R⁴ iscyano.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each independently selectedfrom hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, andC₁-C₄ haloalkoxy; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl, heteroaryl,cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachindependently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q) N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachindependently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰—C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each independently hydrogen,fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(CR^(7a)R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each independently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0- 2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0- 2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach independently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂ orcyano.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) and R^(7b)are each independently selected from C₁-C₇ alkyl, C₁-C₇ haloalkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) and R^(7b)are each independently selected from C₁-C₇ alkyl, C₁-C₇ haloalkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR¹⁰—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) andR^(7b) are each independently selected from C₁-C₇ alkyl, C₁-C₇haloalkyl, cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) andR^(7b) together with the nitrogen atom to which they attach form aheterocycle; R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at eachoccurrence, are independently selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at eachoccurrence is independently selected from hydrogen, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′is aryl, heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) and R^(7b)are each independently selected from C₁-C₇ alkyl, C₁-C₇ haloalkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y- A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) and R^(7b)are each independently selected from C₁-C₇ alkyl, C₁-C₇ haloalkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each independently hydrogen,fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each independently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R^(2a), R^(2b), and R^(2c)are each independently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), or NR¹⁰; R^(7a)and R^(7b) are each independently selected from C₁-C₇ alkyl, cycloalkyl,C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b) together withthe nitrogen atom to which they attach form a heterocycle; R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence, areindependently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach independently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R_(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f) 0, or NR¹⁰; R^(7a)and R^(7b) are each independently selected from C₁-C₇ alkyl, cycloalkyl,C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b) together withthe nitrogen atom to which they attach form a heterocycle; R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence, areindependently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8c)R^(8d))_(q)—Y-A, -A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)),or -A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is abond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y- A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each independently hydrogen,fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each independently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f) 0, or NR¹⁰; R^(7a)and R^(7b) are each independently selected from C₁-C₇ alkyl, cycloalkyl,C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b) together withthe nitrogen atom to which they attach form a heterocycle; R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence, areindependently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R^(2a), R^(2b), and R^(2c)are each independently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), or NR¹⁰; R^(7a)and R^(7b) are each independently selected from C₁-C₇ alkyl, cycloalkyl,C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b) together withthe nitrogen atom to which they attach form a heterocycle; R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence, areindependently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach independently hydrogen, fluoro, or chloro; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f) 0, or NR¹⁰; R^(7a)and R^(7b) are each independently selected from C₁-C₇ alkyl, cycloalkyl,C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b) together withthe nitrogen atom to which they attach form a heterocycle; R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence, areindependently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is —X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)), —X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach hydrogen; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(8a))(R^(8b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A,-A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y- A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is cycloalkyl orheterocycle; and R⁴ is —CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each independently hydrogen,fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each independently hydrogen, fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(2b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R^(2a), R^(2b), and R^(2c)are each independently hydrogen, fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bondCR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) ands R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach independently hydrogen, fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each hydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each hydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach hydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0 -4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b) SO₂R¹¹, and COR¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each independently hydrogen,fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each independently hydrogen, fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachindependently hydrogen, fluoro, or chloro; R^(2a), R^(2b), and R^(2c)are each independently hydrogen, fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach independently hydrogen, fluoro, or chloro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl, heteroaryl, heterocycle, orcycloalkyl; R^(2a), R^(2b), and R^(2c) are each hydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl; R^(2a), R^(2b), andR^(2c) are each hydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl or heteroaryl, substituted with 0-3substituents independently selected from fluoro, chloro, cyano, C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is aryl substituted with 0-2 substituentsindependently selected from fluoro, chloro, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ alkoxyalkyl, and OR⁵; wherein R⁵ is hydrogen, C₁-C₃alkyl, or C₁-C₃ fluoroalkyl; R^(2a), R^(2b), and R^(2c) are eachhydrogen; R3 is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl; R^(2a), R^(2b), and R^(2c) areeach hydrogen; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms; and R⁴ is—CONH₂.

In certain embodiments, R¹ is phenyl substituted with 0-2 substituentsindependently selected from fluoro and methoxy; R^(2a) is hydrogen;R^(2b) and R^(2c) are each independently hydrogen or fluoro; R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₃ alkyl and C₃-C₅ cycloalkyl, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are each independentlyselected from hydrogen and methyl; R⁹ at each occurrence isindependently selected from pyridyl and morpholinyl; wherein 0-1 R⁹groups are present in each R³; m is 0 -1; R¹⁰ is hydrogen or C₁-C₃alkyl; A is pyridyl, pyrimidinyl, morpholinyl, pyrrolidinyl,piperidinyl, pyrazolinyl, tetrahydropyranyl, piperazinyl,1,1-dioxothiomorpholinyl, 1,1-dioxo-1,4-thiazepanyl, 1,4-diazepanyl,1,4-thiazepanyl, 1,4-oxazepanyl, azepanyl, 2-azaspiro[3.3]heptan-2-yl,decahydroquinolyl; wherein A is substituted with 0-2 substituentsindependently selected from fluoro, chloro, cyano, methyl, —CH₂CF₃,methoxy, SO₂Me, acyl, and cyclopropyl; and R⁴ is —CONH₂.

In certain embodiments, R¹ is heteroaryl substituted with 0-1substituents independently selected from C₁-C₃ alkyl; R^(2a) ishydrogen; R^(2b) and R^(2c) are each independently hydrogen or fluoro;R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₃ alkyl and C₃-C₅ cycloalkyl, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are each independentlyselected from hydrogen and methyl; R⁹ at each occurrence isindependently selected from pyridyl and morpholinyl; wherein 0-1 R⁹groups are present in each R³; m is 0 -1; R¹⁰ is hydrogen or C₁-C₃alkyl; A is pyridyl, pyrimidinyl, morpholinyl, pyrrolidinyl,piperidinyl, pyrazolinyl, tetrahydropyranyl, piperazinyl,1,1-dioxothiomorpholinyl, 1,1-dioxo-1,4-thiazepanyl, 1,4-diazepanyl,1,4-thiazepanyl, 1,4-oxazepanyl, azepanyl, 2-azaspiro[3.3]heptan-2-yl,decahydroquinolyl; wherein A is substituted with 0-2 substituentsindependently selected from fluoro, chloro, cyano, methyl, —CH₂CF₃,methoxy, SO₂Me, acyl, and cyclopropyl; and R⁴ is —CONH₂.

Representative compounds of formula (I) include, but are not limited to:

-   1-(4-fluorophenyl)-4-oxo-6-(thiomorpholinomethyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(piperidin-1-ylmethyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-phenethyl-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(4-methylphenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(3-methylphenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(2-methylphenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-4-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-3-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-2-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-yloxy)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(2-fluoro-4-methoxyphenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(3-fluoro-4-methoxyphenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-methoxyphenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-ylamino)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-((pyridin-3-ylmethyl)amino)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(methyl(pyridin-4-yl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(methyl(pyridin-4-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((2-methylpyrimidin-5-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((6-fluoropyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((6-methylpyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(methyl(pyridin-3-yl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((4-cyclopropylpiperazin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((octahydroquinolin-1    (2H)-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((4,7-dimethyl-1,4-diazepan-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((cyclopentyl(methyl)amino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((cyclopropyl(methyl)amino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((1,4-thiazepan-4-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((1,4-oxazepan-4-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-(azepan-1-ylmethyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((4-methoxypiperidin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((4-cyanopiperidin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((4-(methyl    sulfonyl)piperidin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxamide;-   6-((4,4-difluoropiperidin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-(((3,3-difluorocyclobutyl)(methyl)amino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((cis-2,6-dimethylmorpholino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide-   1-(4-fluorophenyl)-4-oxo-6-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxamide;-   6-((4-acetylpiperazin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((1,1-dioxidothiomorpholino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((1,1-dioxido-1,4-thiazepan-4-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((4-methylpiperazin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((6-methylpyridin-3-yl)methoxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(3-methylisothiazol-5-yl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(1-(pyridin-4-yl)ethoxy)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((2-methylpyridin-4-yl)methoxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(pyridin-4-ylmethoxy)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-((2-(pyridin-4-yl)ethyl)amino)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-((2-(pyridin-3-yl)ethyl)amino)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((2-morpholinoethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-((2-methylpyrimidin-5-yl)methoxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(1-(pyridin-3-yl)ethoxy)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(methyl((2-methylpyrimidin-5-yl)methyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(((3-fluoropyridin-4-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(((2-methylpyridin-4-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(((2-(trifluoromethyl)pyridin-4-yl)oxy)methyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(((2-methylpyrimidin-5-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1,4-dihydroquinoline-3-carboxamide;-   6-(((6-chloropyridin-3-yl)oxy)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-3-yl)piperidin-1-yl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(((2-fluoropyridin-3-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-3-yl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(((6-methylpyridin-3-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-(ethyl(pyridin-3-ylmethyl)amino)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-ylmethoxy)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carbonitrile;-   1-(4-fluorophenyl)-6-(((6-fluoropyridin-3-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(2-(2-(trifluoromethyl)pyridin-4-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(2-(5-fluoropyridin-3-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   8-fluoro-1    -(4-fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(3-morpholinopyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   8-fluoro-1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1    -(4-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-6-(2-methylpyrimidin-5-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(pyridin-4-yl)-1,4-dihydroquinoline-3-carboxamide;-   1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxamide;-   (S)-1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   (R)-1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((2,2-dimethylmorpholino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-(((3,3-difluorocyclobutyl)(methyl)amino)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((cis-2,6-dimethylmorpholino)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   8-fluoro-1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((4,4-difluoropiperidin-1-yl)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   6-((3,3-difluoropyrrolidin-1-yl)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;-   7-fluoro-1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;    and-   7-fluoro-1    -(4-fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;

and pharmaceutically acceptable salt thereof.

Compound names are assigned by using Struct=Name naming algorithm aspart of CHEMDRAW® ULTRA v. 12.0.

The compound may exist as a stereoisomer wherein asymmetric or chiralcenters are present. The stereoisomer is “R” or “S” depending on theconfiguration of substituents around the chiral carbon atom. The terms“R” and “S” used herein are configurations as defined in IUPAC 1974Recommendations for Section E, Fundamental Stereochemistry, in PureAppl. Chem., 1976, 45: 13-30. The disclosure contemplates variousstereoisomers and mixtures thereof and these are specifically includedwithin the scope of this invention. Stereoisomers include enantiomersand diastereomers, and mixtures of enantiomers or diastereomers.Individual stereoisomers of the compounds may be prepared syntheticallyfrom commercially available starting materials, which contain asymmetricor chiral centers or by preparation of racemic mixtures followed bymethods of resolution well-known to those of ordinary skill in the art.These methods of resolution are exemplified by (1) attachment of amixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and optional liberation of the optically pure productfrom the auxiliary as described in Furniss, Hannaford, Smith, andTatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5th edition(1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2)direct separation of the mixture of optical enantiomers on chiralchromatographic columns or (3) fractional recrystallization methods.

It should be understood that the compound may possess tautomeric forms,as well as geometric isomers, and that these also constitute an aspectof the invention.

The present disclosure also includes an isotopically-labeled compound,which is identical to those recited in formula (I), but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes suitable for inclusion in the compoundsof the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, and chlorine, such as, but not limited to ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances. Thecompound may incorporate positron-emitting isotopes for medical imagingand positron-emitting tomography (PET) studies for determining thedistribution of receptors. Suitable positron-emitting isotopes that canbe incorporated in compounds of formula (I) are ¹¹C, ¹³N ¹⁵O, and ¹⁸F.Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examplesusing appropriate isotopically-labeled reagent in place ofnon-isotopically-labeled reagent.

A. Allosteric Modulation of mGlu₂

The disclosed compounds may act or function as non-competitiveantagonists, allosteric inhibitors, allosteric antagonists, or negativeallosteric modulators (NAM) of mGlu₂. The compounds may be procognitiveand neuroprotective even in the presence of mGlu₂ dysfunction.

Compounds of formula (I) can inhibit mGlu₂ with an IC₅₀ ranging fromabout 1 nM to about 30 μM. The compounds may have an IC₅₀ of about 30μM, about 29 μM, about 28 μM, about 27 μM, about 26 μM, about 25 μM,about 24 μM, about 23 μM, about 22 μM, about 21 μM, about 20 μM, about19 μM, about 18 μM, about 17 μM, about 16 μM, about 15 μM, about 14 μM,about 13 μM, about 12 μM, about 11 μM, about 10 μM, about 9 μM, about 8μM, about 7 μM, about 6 μM, about 5 μM, about 4 μM, about 3 μM, about 2μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,about 850 nM, about 800 nM, about 750 nM, about 700 nM, about 650 nM,about 600 nM, about 550 nM, about 500 nM, about 450 nM, about 400 nM,about 350 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM,about 100 nM, about 50 nM, about 10 nM, about 5 nM, or about 1 nM.Compounds of formula (I) can inhibit mGlu₂ with an IC50 of less than 30μM, less than 29 μM, less than 28 μM, less than 27 μM, less than 26 μM,less than 25 μM, less than 24 μM, less than 23 μM, less than 22 μM, lessthan 21 μM, less than 20 μM, less than 19 μM, less than 18 μM, less than17 μM, less than 16 μM, less than 15 μM, less than 14 μM, less than 13μM, less than 12 μM, less than 11 μM, less than 10 μM, less than 9 μM,less than 8 μM, less than 7 μM, less than 6 μM, less than 5 μM, lessthan 4 μM, less than 3 μM, less than 2 μM, less than 1 μM, less than 950nM, less than 900 nM, less than 850 nM, less than 800 nM, less than 850nM, less than 800 nM, less than 750 nM, less than 700 nM, less than 650nM, less than 600 nM, less than 550 nM, less than 500 nM, less than 450nM, less than 400 nM, less than 350 nM, less than 300 nM, less than 250nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 50nM, less than 10 nM, less than 5 nM, or less than 1 nM.

Compounds of formula (I) may be selective modulators of mGlu₂ overmGlu₃. The compounds may have a ratio of mGlu₂ IC₅₀ to mGlu₃ EC₅₀ of atleast 100, at least 95, at least 90, at least 85, at least 80, at least75, at least 70, at least 64, at least 60, at least 55, at least 50, atleast 45, at least 40, at least 35, at least 33, at least 31, at least30, at least 29, at least 28, at least 27, at least 26, at least 25, atleast 24, at least 23, at least 22, at least 21, at least 20, at least19, at least 18, at least 17, at least 16, at least 15, at least 14, atleast 13, at least 12, at least 11, at least 10, at least 9, at least 8,at least 7, at least 6, at least 5, at least 4, at least 3, or at least2. Compounds of formula (I) may have a ratio of mGlu₂ IC₅₀ to mGlu₃ EC₅₀of about 100, about 95, about 90, about 85, about 80, about 75, about70, about 64, about 60, about 55, about 50, about 45, about 40, about35, about 33, about 31, about 30, about 29, about 28, about 27, about26, about 25, about 24, about 23, about 22, about 21, about 20, about19, about 18, about 17, about 16, about 15, about 14, about 13, about12, about 11, about 10, about 9, about 8, about 7, about 6, about 5,about 4, about 3, or about 2.

Compounds of formula (I) may be selective modulators of mGlu₂ overmGlu₅. The compounds may have a ratio of mGlu₂ IC₅₀ to mGlu₅ EC₅₀ of atleast 100, at least 95, at least 90, at least 85, at least 80, at least75, at least 70, at least 64, at least 60, at least 55, at least 50, atleast 45, at least 40, at least 35, at least 33, at least 31, at least30, at least 29, at least 28, at least 27, at least 26, at least 25, atleast 24, at least 23, at least 22, at least 21, at least 20, at least19, at least 18, at least 17, at least 16, at least 15, at least 14, atleast 13, at least 12, at least 11, at least 10, at least 9, at least 8,at least 7, at least 6, at least 5, at least 4, at least 3, or at least2. Compounds of formula (I) may have a ratio of mGlu₂ IC₅₀ to mGlu₅ EC₅₀of about 100, about 95, about 90, about 85, about 80, about 75, about70, about 64, about 60, about 55, about 50, about 45, about 40, about35, about 33, about 31, about 30, about 29, about 28, about 27, about26, about 25, about 24, about 23, about 22, about 21, about 20, about19, about 18, about 17, about 16, about 15, about 14, about 13, about12, about 11, about 10, about 9, about 8, about 7, about 6, about 5,about 4, about 3, or about 2.

The disclosed compounds may exist as pharmaceutically acceptable salts.The term “pharmaceutically acceptable salt” refers to salts orzwitterions of the compounds which are water or oil-soluble ordispersible, suitable for treatment of disorders without undue toxicity,irritation, and allergic response, commensurate with a reasonablebenefit/risk ratio and effective for their intended use. The salts maybe prepared during the final isolation and purification of the compoundsor separately by reacting an amino group of the compounds with asuitable acid. For example, a compound may be dissolved in a suitablesolvent, such as but not limited to methanol and water and treated withat least one equivalent of an acid, like hydrochloric acid. Theresulting salt may precipitate out and be isolated by filtration anddried under reduced pressure. Alternatively, the solvent and excess acidmay be removed under reduced pressure to provide a salt. Representativesalts include acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, isethionate, fumarate, lactate, maleate, methanesulfonate,naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate,propionate, succinate, tartrate, thrichloroacetate, trifluoroacetate,glutamate, para-toluenesulfonate, undecanoate, hydrochloric,hydrobromic, sulfuric, phosphoric and the like. The amino groups of thecompounds may also be quaternized with alkyl chlorides, bromides andiodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl,myristyl, stearyl and the like.

Basic addition salts may be prepared during the final isolation andpurification of the disclosed compounds by reaction of a carboxyl groupwith a suitable base such as the hydroxide, carbonate, or bicarbonate ofa metal cation such as lithium, sodium, potassium, calcium, magnesium,or aluminum, or an organic primary, secondary, or tertiary amine.Quaternary amine salts can be prepared, such as those derived frommethylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine, tributylamine, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine,dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine andN,N′-dibenzylethylenediamine, ethylenediamine, ethanolamine,diethanolamine, piperidine, piperazine, and the like.

B. General Synthesis

Compounds of formula (I) may be prepared by synthetic processes or bymetabolic processes. Preparation of the compounds by metabolic processesincludes those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

Compounds of formula (I), wherein the groups R¹, R^(2a), R^(2b), R^(2c),R³, and R⁴ have the meanings as set forth in the Summary of theInvention section unless otherwise noted, can be synthesized as shown inSchemes 1-18.

Abbreviations which have been used in the descriptions of the Schemesthat follow are: D^(t)BAD for di-tert-butylazodicarboxylate; BuLi forbutyllithium; dba for dibenzylideneacetone; DIEA fordiisopropylethylamine; DME for dimethoxyethane; DMF fordimethylformamide; dppf for 1,1′-bis(diphenylphosphino)ferrocene; EDCfor N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; HATUforN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide; HOBt for 1-hydroxybenzotriazole; Me₂CO foracetone; MeOH for methanol; NEt₃ for triethylamine; n-PrOH forn-propanol; PhMe for toluene; tBuXPhos for2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl; THF fortetrahydrofuran; XantPhos for4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

As shown in Scheme 1, intermediate v, wherein each R² is as defined inthe Summary of the Invention, can be prepared from substituted benzoylchloride i. Treatment of 3-ethoxy-3-oxopropanoic acid ii withbutyllithium, followed by addition of i, can result in formation ofβ-ketoester iii. β-ketoester iii can be treated with DMF-DMA (iv),followed by addition of R¹NH₂, wherein R¹ is as defined in the Summaryof the Invention, to provide intermediate v.

Scheme 2 illustrates the conversion of intermediate v to intermediatevi. Intermediate v can be treated with a solution of ammonia in methanolwith heating to give intermediate vi.

Scheme 3 illustrates the preparation of intermediate x from intermediatev and the preparation of intermediate xi from intermediate vi. Bromidesv and vi may be converted to alkenes viii and ix, respectively, via apalladium catalyzed coupling reaction with potassiumvinyltrifluoroborate vii, wherein R^(8a) is as defined in the Summary ofthe Invention. Treatment of intermediates viii and ix with osmiumtetroxide and 4-methylmorpholine N-oxide (NMO) can form thecorresponding diols, which can be reacted in situ with sodium(meta)periodate to afford intermediates x and xi, respectively.

Scheme 4 illustrates the conversion of intermediate x to intermediatexiv. Intermediate x can be treated with an amine xii, wherein R^(7a) andR^(7b) are as defined in the Summary of the Invention, and a reagentxiii, wherein M is a group that renders R^(8b) nucleophilic, whereinR^(8b) is as defined in the Summary of the Invention, to provideintermediate xiv.

Scheme 5 illustrates the conversion of intermediate x to intermediatexv. Intermediate x can be treated with a reagent xiii, wherein M is agroup that renders R^(8b) nucleophilic, wherein R^(8b) is as defined inthe Summary of the Invention, to provide intermediate xv.

Scheme 6 illustrates the conversion of intermediate v to intermediatexvii. Intermediate v can be converted to intermediate xvi via apalladium catalyzed hydroxylation. Intermediate xvi can be treated withacid in methanol with heating to afford intermediate xvii.

Scheme 7 illustrates the preparation of intermediate xx fromintermediate xvii and the preparation of intermediate xxi fromintermediate xvii. Intermediate xvii can be reacted in a Mitsunobureaction with alcohols xviii and xix, wherein R^(7a), R^(7b), R^(8a),R^(8b), R^(8c), R^(8d), Z, p, q, Y, and A are as defined in the Summaryof the Invention, to produce intermediates xx and xxi, respectively.

Scheme 8 illustrates the synthesis of intermediate xxiii fromintermediate xv. Intermediate xv can be reacted in a Mitsunobu reactionwith alcohol xxii, wherein, A is as defined in the Summary of theInvention, to produce intermediate xxiii, respectively.

Scheme 9 illustrates the preparation of intermediate xxviii fromintermediate v, the preparation of intermediate xxix from intermediatev, the preparation of intermediate xxx from intermediate v, and thepreparation of intermediate xxxi from intermediate v. Intermediate v maybe reacted with amines xxiv, xxv, xxvi, and xxvii, wherein R^(7a),R^(7b), R^(8a), R^(8b), R^(8c), R^(8d), Z, p, q, Y, and A are as definedin the Summary of the Invention, in a Buchwald-Hartwig palladiumcatalyzed coupling to produce intermediates xxviii, xxix, xxx, and xxxi,respectively.

Scheme 10 illustrates the synthesis of intermediate xxxiv fromintermediate v and the preparation of intermediate xxxv fromintermediate v. Intermediate v can be reacted with alkynes xxxii andxxxiii, wherein R^(7a), R^(7b), R^(8a), R^(8b), R^(8c), R^(8d), Z, q, Y,and A are as defined in the Summary of the Invention and wherein p is 0or 1, in a Sonogashira coupling to provide intermediates xxxiv and xxxv,respectively.

Scheme 11 illustrates the conversion of intermediate v to intermediatexxxviii. Reaction of intermediate v with ethynyltrimethylsilane in aSonogashira coupling can provide intermediate xxxvi. Treatment ofintermediate xxxvi with tetrabutylammonium fluoride can yieldintermediate xxxvii. Coupling of intermediate xxxvii with A—X, wherein Ais as defined in the Summary of the Invention and wherein X is chloride,bromide, iodide, or trifluoromethanesulfonate, under Sonogashiraconditions can afford intermediate xxxviii.

Scheme 12 illustrates the synthesis of intermediate xxxix fromintermediate xxxiv, the preparation of intermediate xl from intermediatexxxv, and the preparation of intermediate xli from intermediate xxxviii.Intermediates xxxiv, xxxv, and xxxviii can be reduced via a palladiumcatalyzed hydrogenation to afford intermediates xxxix, xl, and xli,respectively.

As illustrated in Scheme 13, the compound of formula (I) can be preparedfrom intermediate xlii. Treatment of intermediate xlii, wherein R³ is asdefined in the Summary of the invention, with ammonia in methanol withheating can provide the compound of formula (I).

Alternatively, the compound of formula (I) can be prepared fromintermediate xlii, as illustrated in Scheme 14, by a two-step process.Hydrolysis of intermediate xlii, wherein R³ is as defined in the Summaryof the invention, with aqueous hydroxide can provide intermediate acidxliii. Intermediate xliii can be converted to the compound of formula(I) using ammonium chloride and a suitable coupling reagent.

As illustrated in Scheme 15, the compound of formula (I) can also beprepared from intermediate vi. Reaction of intermediate vi with alcoholssuch as xviii and xix, wherein R^(7a), R^(7b), R^(8a), R^(8b), R^(8c),R^(8d), Z, q, Y, and A are as defined in the Summary of the Invention,in an Ullmann coupling can afford the compound of formula (I).

Alternatively, as illustrated in Scheme 16, the compound of formula (I)can be prepared from intermediate vi. Intermediate vi can be reacted ina palladium catalyzed Suzuki coupling reaction with reagents such asxliv or xlv, wherein R³ is as defined in the Summary of the invention,to yield the compound of formula (I).

As illustrated in Scheme 17, the compound of formula (I) can also beprepared from intermediate ix. Intermediate ix can be treated with anamine xii, wherein R^(7a) and R^(7b) are as defined in the Summary ofthe Invention, and a reagent xiii, wherein M is a group that rendersR^(8b) nucleophilic, wherein R^(8b) is as defined in the Summary of theInvention, to provide the compound of formula (I).

As illustrated in Scheme 18, the compound of formula (I), wherein R⁴ iscyano, can be prepared from intermediate vi. The primary amide of vi canbe dehydrated through treatment with an appropriate reagent such ascyanuric chloride to afford intermediate xlvi. Conversion ofintermediate xlvi into the compound of formula (I) can be accomplishedusing methods analogous to those described in Schemes 3-12 and Schemes15-17.

The compounds and intermediates may be isolated and purified by methodswell-known to those skilled in the art of organic synthesis. Examples ofconventional methods for isolating and purifying compounds can include,but are not limited to, chromatography on solid supports such as silicagel, alumina, or silica derivatized with alkylsilane groups, byrecrystallization at high or low temperature with an optionalpretreatment with activated carbon, thin-layer chromatography,distillation at various pressures, sublimation under vacuum, andtrituration, as described for instance in “Vogel's Textbook of PracticalOrganic Chemistry”, 5th edition (1989), by Furniss, Hannaford, Smith,and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE,England.

A disclosed compound may have at least one basic nitrogen whereby thecompound can be treated with an acid to form a desired salt. Forexample, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic,carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic,hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric,camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, andthe like.

Optimum reaction conditions and reaction times for each individual stepcan vary depending on the particular reactants employed and substituentspresent in the reactants used. Specific procedures are provided in theExamples section. Reactions can be worked up in the conventional manner,e.g. by eliminating the solvent from the residue and further purifiedaccording to methodologies generally known in the art such as, but notlimited to, crystallization, distillation, extraction, trituration andchromatography. Unless otherwise described, the starting materials andreagents are either commercially available or can be prepared by oneskilled in the art from commercially available materials using methodsdescribed in the chemical literature.

Starting materials, if not commercially available, can be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that cannot be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which canbe found in PGM Wuts and TW Greene, in Greene's book titled ProtectiveGroups in Organic Synthesis (4^(th) ed.), John Wiley & Sons, NY (2006),which is incorporated herein by reference in its entirety. Synthesis ofthe compounds of the invention can be accomplished by methods analogousto those described in the synthetic schemes described hereinabove and inspecific examples.

When an optically active form of a disclosed compound is required, itcan be obtained by carrying out one of the procedures described hereinusing an optically active starting material (prepared, for example, byasymmetric induction of a suitable reaction step), or by resolution of amixture of the stereoisomers of the compound or intermediates using astandard procedure (such as chromatographic separation,recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, itcan be obtained by carrying out one of the above procedures using a puregeometric isomer as a starting material, or by resolution of a mixtureof the geometric isomers of the compound or intermediates using astandard procedure such as chromatographic separation.

It can be appreciated that the synthetic schemes and specific examplesas described are illustrative and are not to be read as limiting thescope of the invention as it is defined in the appended claims. Allalternatives, modifications, and equivalents of the synthetic methodsand specific examples are included within the scope of the claims.

3. Pharmaceutical Compositions

The disclosed compounds may be incorporated into pharmaceuticalcompositions suitable for administration to a subject (such as apatient, which may be a human or non-human).

The pharmaceutical compositions may include a “therapeutically effectiveamount” or a “prophylactically effective amount” of the agent. A“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount of thecomposition may be determined by a person skilled in the art and mayvary according to factors such as the disease state, age, sex, andweight of the individual, and the ability of the composition to elicit adesired response in the individual. A therapeutically effective amountis also one in which any toxic or detrimental effects of a compound ofthe invention [e.g., a compound of formula (I)] are outweighed by thetherapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result. Typically,since a prophylactic dose is used in subjects prior to or at an earlierstage of disease, the prophylactically effective amount will be lessthan the therapeutically effective amount.

For example, a therapeutically effective amount of a compound of formula(I), may be about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about650 mg/kg, about 40 mg/kg to about 600 mg/kg, about 45 mg/kg to about550 mg/kg, about 50 mg/kg to about 500 mg/kg, about 55 mg/kg to about450 mg/kg, about 60 mg/kg to about 400 mg/kg, about 65 mg/kg to about350 mg/kg, about 70 mg/kg to about 300 mg/kg, about 75 mg/kg to about250 mg/kg, about 80 mg/kg to about 200 mg/kg, about 85 mg/kg to about150 mg/kg, and about 90 mg/kg to about 100 mg/kg.

The pharmaceutical compositions may include pharmaceutically acceptablecarriers. The term “pharmaceutically acceptable carrier,” as usedherein, means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as, but not limited to, lactose,glucose and sucrose; starches such as, but not limited to, corn starchand potato starch; cellulose and its derivatives such as, but notlimited to, sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as, but not limited to, cocoa butter and suppository waxes; oilssuch as, but not limited to, peanut oil, cottonseed oil, safflower oil,sesame oil, olive oil, corn oil and soybean oil; glycols; such aspropylene glycol; esters such as, but not limited to, ethyl oleate andethyl laurate; agar; buffering agents such as, but not limited to,magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol, and phosphatebuffer solutions, as well as other non-toxic compatible lubricants suchas, but not limited to, sodium lauryl sulfate and magnesium stearate, aswell as coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

Thus, the compounds and their physiologically acceptable salts andsolvates may be formulated for administration by, for example, soliddosing, eyedrop, in a topical oil-based formulation, injection,inhalation (either through the mouth or the nose), implants, or oral,buccal, parenteral, or rectal administration. Techniques andformulations may generally be found in “Remington's PharmaceuticalSciences”, (Meade Publishing Co., Easton, Pa.). Therapeutic compositionsmust typically be sterile and stable under the conditions of manufactureand storage.

The route by which the disclosed compounds are administered and the formof the composition will dictate the type of carrier to be used. Thecomposition may be in a variety of forms, suitable, for example, forsystemic administration (e.g., oral, rectal, nasal, sublingual, buccal,implants, or parenteral) or topical administration (e.g., dermal,pulmonary, nasal, aural, ocular, liposome delivery systems, oriontophoresis).

Carriers for systemic administration typically include at least one ofdiluents, lubricants, binders, disintegrants, colorants, flavors,sweeteners, antioxidants, preservatives, glidants, solvents, suspendingagents, wetting agents, surfactants, combinations thereof, and others.All carriers are optional in the compositions.

Suitable diluents include sugars such as glucose, lactose, dextrose, andsucrose; diols such as propylene glycol; calcium carbonate; sodiumcarbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. Theamount of diluent(s) in a systemic or topical composition is typicallyabout 50 to about 90%.

Suitable lubricants include silica, talc, stearic acid and its magnesiumsalts and calcium salts, calcium sulfate; and liquid lubricants such aspolyethylene glycol and vegetable oils such as peanut oil, cottonseedoil, sesame oil, olive oil, corn oil and oil of theobroma. The amount oflubricant(s) in a systemic or topical composition is typically about 5to about 10%.

Suitable binders include polyvinyl pyrrolidone; magnesium aluminumsilicate; starches such as corn starch and potato starch; gelatin;tragacanth; and cellulose and its derivatives, such as sodiumcarboxymethylcellulose, ethyl cellulose, methylcellulose,microcrystalline cellulose, and sodium carboxymethylcellulose. Theamount of binder(s) in a systemic composition is typically about 5 toabout 50%.

Suitable disintegrants include agar, alginic acid and the sodium saltthereof, effervescent mixtures, croscarmelose, crospovidone, sodiumcarboxymethyl starch, sodium starch glycolate, clays, and ion exchangeresins. The amount of disintegrant(s) in a systemic or topicalcomposition is typically about 0.1 to about 10%.

Suitable colorants include a colorant such as an FD&C dye. When used,the amount of colorant in a systemic or topical composition is typicallyabout 0.005 to about 0.1%.

Suitable flavors include menthol, peppermint, and fruit flavors. Theamount of flavor(s), when used, in a systemic or topical composition istypically about 0.1 to about 1.0%.

Suitable sweeteners include aspartame and saccharin. The amount ofsweetener(s) in a systemic or topical composition is typically about0.001 to about 1%.

Suitable antioxidants include butylated hydroxyanisole (“BHA”),butylated hydroxytoluene (“BHT”), and vitamin E. The amount ofantioxidant(s) in a systemic or topical composition is typically about0.1 to about 5%.

Suitable preservatives include benzalkonium chloride, methyl paraben andsodium benzoate. The amount of preservative(s) in a systemic or topicalcomposition is typically about 0.01 to about 5%.

Suitable glidants include silicon dioxide. The amount of glidant(s) in asystemic or topical composition is typically about 1 to about 5%.

Suitable solvents include water, isotonic saline, ethyl oleate,glycerine, hydroxylated castor oils, alcohols such as ethanol, andphosphate buffer solutions. The amount of solvent(s) in a systemic ortopical composition is typically from about 0 to about 100%.

Suitable suspending agents include AVICEL RC-591 (from FMC Corporationof Philadelphia, Pa.) and sodium alginate. The amount of suspendingagent(s) in a systemic or topical composition is typically about 1 toabout 8%.

Suitable surfactants include lecithin, Polysorbate 80, and sodium laurylsulfate, and the TWEENS from Atlas Powder Company of Wilmington, Del.Suitable surfactants include those disclosed in the C.T.F.A. CosmeticIngredient Handbook, 1992, pp. 587-592; Remington's PharmaceuticalSciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1,Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. Theamount of surfactant(s) in the systemic or topical composition istypically about 0.1% to about 5%.

Although the amounts of components in the systemic compositions may varydepending on the type of systemic composition prepared, in general,systemic compositions include 0.01% to 50% of active [e.g., compound offormula (I)] and 50% to 99.99% of one or more carriers. Compositions forparenteral administration typically include 0.1% to 10% of actives and90% to 99.9% of a carrier including a diluent and a solvent.

Compositions for oral administration can have various dosage forms. Forexample, solid forms include tablets, capsules, granules, and bulkpowders. These oral dosage forms include a safe and effective amount,usually at least about 5%, and more particularly from about 25% to about50% of actives. The oral dosage compositions include about 50% to about95% of carriers, and more particularly, from about 50% to about 75%.

Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed. Tablets typicallyinclude an active component, and a carrier comprising ingredientsselected from diluents, lubricants, binders, disintegrants, colorants,flavors, sweeteners, glidants, and combinations thereof. Specificdiluents include calcium carbonate, sodium carbonate, mannitol, lactoseand cellulose. Specific binders include starch, gelatin, and sucrose.Specific disintegrants include alginic acid and croscarmelose. Specificlubricants include magnesium stearate, stearic acid, and talc. Specificcolorants are the FD&C dyes, which can be added for appearance. Chewabletablets preferably contain sweeteners such as aspartame and saccharin,or flavors such as menthol, peppermint, fruit flavors, or a combinationthereof.

Capsules (including implants, time release and sustained releaseformulations) typically include an active compound [e.g., a compound offormula (I)], and a carrier including one or more diluents disclosedabove in a capsule comprising gelatin. Granules typically comprise adisclosed compound, and preferably glidants such as silicon dioxide toimprove flow characteristics. Implants can be of the biodegradable orthe non-biodegradable type.

The selection of ingredients in the carrier for oral compositionsdepends on secondary considerations like taste, cost, and shelfstability, which are not critical for the purposes of this invention.

Solid compositions may be coated by conventional methods, typically withpH or time-dependent coatings, such that a disclosed compound isreleased in the gastrointestinal tract in the vicinity of the desiredapplication, or at various points and times to extend the desiredaction. The coatings typically include one or more components selectedfrom the group consisting of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethylcellulose, EUDRAGIT coatings (available from Rohm & Haas G.M.B.H. ofDarmstadt, Germany), waxes and shellac.

Compositions for oral administration can have liquid forms. For example,suitable liquid forms include aqueous solutions, emulsions, suspensions,solutions reconstituted from non-effervescent granules, suspensionsreconstituted from non-effervescent granules, effervescent preparationsreconstituted from effervescent granules, elixirs, tinctures, syrups,and the like. Liquid orally administered compositions typically includea disclosed compound and a carrier, namely, a carrier selected fromdiluents, colorants, flavors, sweeteners, preservatives, solvents,suspending agents, and surfactants. Peroral liquid compositionspreferably include one or more ingredients selected from colorants,flavors, and sweeteners.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically include one or more of soluble filler substancessuch as diluents including sucrose, sorbitol and mannitol; and binderssuch as acacia, microcrystalline cellulose, carboxymethyl cellulose, andhydroxypropyl methylcellulose. Such compositions may further includelubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

The disclosed compounds can be topically administered. Topicalcompositions that can be applied locally to the skin may be in any formincluding solids, solutions, oils, creams, ointments, gels, lotions,shampoos, leave-on and rinse-out hair conditioners, milks, cleansers,moisturizers, sprays, skin patches, and the like. Topical compositionsinclude: a disclosed compound [e.g., a compound of formula (I)], and acarrier. The carrier of the topical composition preferably aidspenetration of the compounds into the skin. The carrier may furtherinclude one or more optional components.

The amount of the carrier employed in conjunction with a disclosedcompound is sufficient to provide a practical quantity of compositionfor administration per unit dose of the medicament. Techniques andcompositions for making dosage forms useful in the methods of thisinvention are described in the following references: ModernPharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

A carrier may include a single ingredient or a combination of two ormore ingredients. In the topical compositions, the carrier includes atopical carrier. Suitable topical carriers include one or moreingredients selected from phosphate buffered saline, isotonic water,deionized water, monofunctional alcohols, symmetrical alcohols, aloevera gel, allantoin, glycerin, vitamin A and E oils, mineral oil,propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castoroil, combinations thereof, and the like. More particularly, carriers forskin applications include propylene glycol, dimethyl isosorbide, andwater, and even more particularly, phosphate buffered saline, isotonicwater, deionized water, monofunctional alcohols, and symmetricalalcohols.

The carrier of a topical composition may further include one or moreingredients selected from emollients, propellants, solvents, humectants,thickeners, powders, fragrances, pigments, and preservatives, all ofwhich are optional.

Suitable emollients include stearyl alcohol, glyceryl monoricinoleate,glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil,cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate,isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate,decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropylstearate, butyl stearate, polyethylene glycol, triethylene glycol,lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylatedlanolin alcohols, petroleum, mineral oil, butyl myristate, isostearicacid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyllactate, decyl oleate, myristyl myristate, and combinations thereof.Specific emollients for skin include stearyl alcohol andpolydimethylsiloxane. The amount of emollient(s) in a skin-based topicalcomposition is typically about 5% to about 95%.

Suitable propellants include propane, butane, isobutane, dimethyl ether,carbon dioxide, nitrous oxide, and combinations thereof. The amount ofpropellant(s) in a topical composition is typically about 0% to about95%.

Suitable solvents include water, ethyl alcohol, methylene chloride,isopropanol, castor oil, ethylene glycol monoethyl ether, diethyleneglycol monobutyl ether, diethylene glycol monoethyl ether,dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinationsthereof. Specific solvents include ethyl alcohol and homotopic alcohols.The amount of solvent(s) in a topical composition is typically about 0%to about 95%.

Suitable humectants include glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate,gelatin, and combinations thereof. Specific humectants include glycerin.The amount of humectant(s) in a topical composition is typically 0% to95%.

The amount of thickener(s) in a topical composition is typically about0% to about 95%.

Suitable powders include beta-cyclodextrins, hydroxypropylcyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums,colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammoniumsmectites, trialkyl aryl ammonium smectites, chemically-modifiedmagnesium aluminum silicate, organically-modified Montmorillonite clay,hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodiumcarboxymethyl cellulose, ethylene glycol monostearate, and combinationsthereof. The amount of powder(s) in a topical composition is typically0% to 95%.

The amount of fragrance in a topical composition is typically about 0%to about 0.5%, particularly, about 0.001% to about 0.1%.

Suitable pH adjusting additives include HCl or NaOH in amountssufficient to adjust the pH of a topical pharmaceutical composition.

4. Methods of Treatment

The disclosed compounds and compositions may be used in methods fortreatment of mGlu₂ related medical disorders and/or diseases. Themethods of treatment may comprise administering to a subject in need ofsuch treatment a composition comprising a therapeutically effectiveamount of the compound of formula (I).

The compositions can be administered to a subject in need thereof tomodulate mGlu₂, for a variety of diverse biological processes. Thepresent disclosure is directed to methods for administering thecomposition to inhibit mGlu₂, a GPCR that plays a role in synapticplasticity, which directly effects cognitive function and memory, forexample.

The compositions may be useful for treating and preventing certaindiseases and disorders in humans and animals related to mGlu₂dysfunction. Treatment or prevention of such diseases and disorders canbe effected by modulating mGlu₂ in a subject, by administering acompound or composition of the invention, either alone or in combinationwith another active agent as part of a therapeutic regimen to a subjectin need thereof.

a. Depression

Antidepressant-like effects of the mGlu_(2/3) receptor antagonists,MGS0039 and LY341495, were first demonstrated in the rat forced swimtest (FST) and mouse tail-suspension test (TST) using normal animals(Chaki et al. Neuropharmacology, 2004, 46, 457-467). More recently,studies have attempted to evaluate the effects of these drugs inparadigms implicated in the etiology of human depression. MGS0039exhibited antidepressant effects in the learned helplessness test wheretreatment with MGS0039 for 7 days significantly reduced the number ofescape failures (Yoshimizu et al. Psychopharmacology, 2006, 186,587-593). Palucha-Poniewiera et al. Psychopharmacology, 2010, 212,523-535 evaluated a potential antidepressant-like effect of MGS0039 inthe olfactory bulbectomy (OB) model of depression in rats. A surgicallesion of the olfactory bulbs in animals is known to induce significantbehavioral, physiological, endocrine and immune changes, many of whichare qualitatively similar to those observed in depressive patients.Repeated administration of MGS0039 for 14 days attenuated thehyperactivity of olfactory bulbectomized rats in the open field test andattenuated the learning deficit in the passive avoidance test.

Kawasaki et al. Neuropharmacology, 2011, 60, 397-404 also examined theeffect of MGS0039 on behaviors of social isolation-reared mice in theFST. Rearing rodents in isolation after weaning is known to lead tochanges in brain neurochemistry that produce perturbations in behavior.Post-weaning chronic social isolation for more than 6 weeks increasedimmobility in the FST, suggesting that isolation rearing causeddepression-like behavior. MGS0039 reversed the increased immobility ofsocial isolation reared mice in the test.

Campo, B. et al. J. Neurogenetics 2011, 25, 152-166, demonstrated aselective group II (mGlu₂ and mGlu₃) negative allosteric modulator(RO4491533) to be effective in several in vitro biochemical assays andin vivo models of depression. RO4491533 was shown to engage the centralmGlu₂ and mGlu₃ receptors as the compound reversed the hypolocomotoreffect of an mGlu_(2/3) agonist (LY379268) in a target-specific manner.The known group II mGlu_(2/3) antagonist LY341495 achieved the sameresult. RO4491533 and LY341495 dose-dependently reduced immobility timeof C57B16/J mice in the FST. RO4491533 and LY341495 were also active inthe tail suspension test in a line of Helpless (H) mice, a putativegenetic model of depression.

Blockade of mGlu_(2/3) receptors and ketamine may converge to the sameneuronal circuits, which include activation of AMPA receptor and mTORsignaling. Because both AMPA receptor stimulation and subsequent mTORsignaling activation are presumed to be involved in rapid action ofketamine for patients with treatment-resistant depression (TRD),mGlu_(2/3) receptor antagonists could exert the same effects in humans.This assumption is underpinned by several animal studies. First, themGlu_(2/3) receptor antagonist MGS0039 exhibited antidepressant effectsin an animal model (the learned helplessness paradigm) which isrefractory to currently prescribed antidepressants (Yoshimizu et al.Psychopharmacology, 2006, 186, 587-593). Second, although evidence ofrapid onset of action with mGlu_(2/3) receptor antagonists are absent,an AMPA receptor potentiator (AMPA receptor potentiation mediatesantidepressant effects of mGlu_(2/3) receptor antagonists) showed fastereffects (during the first week of treatment) compared to fluoxetine(after two weeks) in a dominant-submissive test (Knapp et al. Eur. J.Pharmacol. 2002, 440, 121-125). Moreover, LY341495 exhibited a potentantidepressant effect in helpless mice following acute administration,while fluoxetine exerted a full antidepressant effect following chronic(21 days) treatment (Campo, B. et al. J. Neurogenetics 2011, 25,152-166; El Yacoubi et al. PNAS, 2003, 100, 6227-6232). Therefore,blockade of mGlu_(2/3) receptors may show rapid and potentantidepressant effects in humans.

b. Cognitive Disorders

Woltering et al. Bioorg. Med. Chem. Lett. 2010, 20, 6969-74,demonstrated that a negative allosteric modulator of mGlu_(2/3) reversedmGlu_(2/3) agonist or scopolamine-induced working memory deficits in thedelayed match to position (DMTP) task in rodents, a measure of workingmemory. Additionally, Woltering demonstrated a synergistic reversal ofscopolamine-induced deficits in DMTP when low doses of a negativeallosteric modulator of mGlu_(2/3) were combined with a threshold doseof the acetylcholinesterase inhibitor donezepil. Given the efficacy ofdonepezil and other acetylcholinesterase inhibitors in the treatment ofthe cognitive impairments in Alzheimer's disease, negative allostericmodulators of mGlu₂ may have efficacy as cognitive enhancers.

c. Obsessive-Compulsive Disorder

Shimazaki, T. et al. Eur. J. Pharmacol. 2004, 501, 121-125, demonstratedthat MGS0039 induced glutamatergic change in mice, resulting inanti-obsessive-compulsive disorder activity. In these studies, amarble-burying behavioral test was utilized as a model forobsessive-compulsive disorder. The marble-burying behavior test isrecognized as a useful model for evaluating the clinical potential ofanti-obsessive-compulsive disorder drugs. Specifically, MGS0039 treatedmice exhibited reduced marble-burying behavior in a significant and dosedependent manner, while no significant change was observed inspontaneous locomotor activity. In addition, LY341495, another potentantagonist of group II mGlu receptors, was also shown to significantlyreduce marble-burying behavior in treated mice.

d. Alzheimer's Disease

Kim, S. H. et al. Moecular Psychiatry 2014, 1-8, have assessed thetherapeutic potential of chronic pharmacological inhibition of group IImGlu receptors (mGlu₂ and mGlu₃) with a group II mGlu receptorantagonist in an APP transgenic mouse model that develops impairedlearning behavior in relation to accumulation of mutant Aβ oligomersthat never form amyloid plaques. Once-daily dosing of the orallybioavailable prodrug, BCI-838, delivered a sufficient brainconcentration of its active metabolite BCI-632 to inhibit group II mGlureceptors for 22 hours. Three months of treatment with BCI-838 providedanxiolytic effects, reversed Dutch APP transgene-associated learning andmemory impairment, and decreased the levels of monomeric and oAβpeptides in the hippocampus and cortex of the two different AD mousemodels. Notably, BCI-838 administration stimulated hippocampalprogenitor cell proliferation in both wild-type and Alzheimer's diseasedmice for 3 months, which resulted in significantly increased numbers ofnewborn neurons in the hippocampi of Dutch APP transgenic mice. Inaddition to treatment, the proneurogenic properties make the compoundattractive for potential use in reversing some of the early symptoms ofAlzheimer's disease (AD), possibly through reparative effects of thenewborn neurons. These findings suggest that chronic pharmacologicalinhibition of group II mGlu receptors has the potential to be adisease-modifying treatment for AD that targets cognitive/emotionaldefects and modulates neurogenesis.

Additional studies by Caraci, F. et al Mol. Pharmacol. 2011, 79,618-626, showed that a positive allosteric modulator of mGlu₂ (LY566332)amplified Aβ-induced neurodegeneration, but this effect was prevented bythe mGlu_(2/3) receptor antagonist, LY341495.

e. Anxiety

Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593 alsodemonstrated the anxiolytic effects of MGS0039, a potent antagonist ofgroup II mGlu receptors (mGlu₂ and mGlu₃), by use of a conditioned fearstress (CFS) model, which represents emotional abnormality, includinganxiety. The CFS model reflects psychological stress without physicalstimuli, and is useful in predicting the clinical efficacy of anxiolyticdrugs. In these studies, MGS0039 significantly decreased freezingbehavior, as did diazepam and fluvoxamine, indicating theanxiolytic-like potential of MGS0039. The mGlu₂₃ receptors inhibitneurotransmitter release as autoreceptors located on glutamatergicterminals and treatment with mGlu_(2/3) antagonists such as MGS0039 invivo led to an increase in extracellular glutamate. Therefore, themoderate elevation of glutamate levels in specific areas of the brain byMGS0039 may cause the anxiolytic-like effects seen in the CFS model.These results suggest that the blockade of mGlu_(2/3) with MGS0039 maybe effective in the treatment of anxiety disorders.

f. Modes of Administration

Methods of treatment may include any number of modes of administering adisclosed composition. Modes of administration may include tablets,pills, dragees, hard and soft gel capsules, granules, pellets, aqueous,lipid, oily or other solutions, emulsions such as oil-in-wateremulsions, liposomes, aqueous or oily suspensions, syrups, elixirs,solid emulsions, solid dispersions or dispersible powders. For thepreparation of pharmaceutical compositions for oral administration, theagent may be admixed with commonly known and used adjuvants andexcipients such as for example, gum arabic, talcum, starch, sugars (suchas, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-activeagents, magnesium stearate, aqueous or non-aqueous solvents, paraffinderivatives, cross-linking agents, dispersants, emulsifiers, lubricants,conserving agents, flavoring agents (e.g., ethereal oils), solubilityenhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailabilityenhancers (e.g. Gelucire™). In the pharmaceutical composition, the agentmay also be dispersed in a microparticle, e.g. a nanoparticulatecomposition.

For parenteral administration, the agent can be dissolved or suspendedin a physiologically acceptable diluent, such as, e.g., water, buffer,oils with or without solubilizers, surface-active agents, dispersants oremulsifiers. As oils for example and without limitation, olive oil,peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil maybe used. More generally spoken, for parenteral administration, the agentcan be in the form of an aqueous, lipid, oily or other kind of solutionor suspension or even administered in the form of liposomes ornano-suspensions.

The term “parenterally,” as used herein, refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

g. Combination Therapies

Additional therapeutic agent(s) may be administered simultaneously orsequentially with the disclosed compounds and compositions. Sequentialadministration includes administration before or after the disclosedcompounds and compositions. In some embodiments, the additionaltherapeutic agent or agents may be administered in the same compositionas the disclosed compounds. In other embodiments, there may be aninterval of time between administration of the additional therapeuticagent and the disclosed compounds. In some embodiments, administrationof an additional therapeutic agent with a disclosed compound may allowlower doses of the other therapeutic agents and/or administration atless frequent intervals. When used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula (I). The abovecombinations include combinations of a compound of the present inventionnot only with one other active compound, but also with two or more otheractive compounds. For example, the compound of Formula (I) can becombined with a variety of antidepressants, Alzheimer's diseasemedications, and anxiolytics.

The compound of Formula (I) can be combined with the followingantidepressants, but not limited to: Selective serotonin reuptakeinhibitors (SSRIs) such as citalopram, dapoxetine, escitalopram,fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, andzimelidine; Serotonin-norepinephrine reuptake inhibitors (SNRIs) such asvenlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran,and sibutramine; Noradrenergic and specific serotonergic antidepressants(NaSSAs) or tetracyclic antidepressants (TeCAs) such as aptazapine,esmirtazapine, mianserin, mirtazapine, and setiptiline; Serotoninantagonist and reuptake inhibitors (SARIs) such as etoperidone,lorpiprazole, mepiprazole, nefazodone, trazodone, vilazodone, andniaprazine; Norepinephrine-dopamine reuptake inhibitors (NDRIs) such asarmodafinil, bupropion, desoxypipradrol, dexmethylphenidate,methylphenidate, modafinil, prolintane, and tametraline;Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs) such asnefopam, amitifadine, tesofensine, and tedatioxetine; Tricyclicantidepressants (TCAs) such as clomipramine, desipramine, imipramine,dibenzepin, lofepramine, nortriptyline, protriptyline, amitriptyline,amitriptylinoxide, amoxapine, butriptyline, demexiptiline, dimetacrine,dosulepin, doxepin, imipraminoxide, melitracen, metapramine,nitroxazepine, noxiptiline, pipofezine, propizepine, quinupramine,amineptine, iprindole, opipramol, tianeptine, and trimipramine; andNegative allosteric modulators of metabotropic glutamate receptor 5(mGlus) such as mavoglurant, basimglurant, dipraglurant, STX107, andN-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide.

The compound of Formula (I) can be combined with the followingAlzheimer's disease medications, but not limited to:Acetylcholinesterase inhibitors such as tacrine, rivastigmine,galantamine, donepezil, edrophonium, physostigmine, pyridostigmine,ambenonium, rivastigmine, ladostigil, and ungeremine; and NMDA receptorantagonists such as memantine, amantadine, delucemine, and ketamine.

The compound of Formula (I) can be combined with the followinganxiolytics, but not limited to: buspirone, tandosprione, gepirone,adaptol, afobazole, hyroxyzine, validol, melatonin, and benzodiazepinessuch as alprazolam, chlordiazepoxide, clonazepam, diazepam, etizolam,lorazepam, oxazepam, and tofisopam.

The disclosed compounds may be included in kits comprising the compound[e.g., one or more compounds of formula (I)], a systemic or topicalcomposition described above, or both; and information, instructions, orboth that use of the kit will provide treatment for medical conditionsin mammals (particularly humans). The information and instructions maybe in the form of words, pictures, or both, and the like. In addition orin the alternative, the kit may include the medicament, a composition,or both; and information, instructions, or both, regarding methods ofapplication of medicament, or of composition, preferably with thebenefit of treating or preventing medical conditions in mammals (e.g.,humans).

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

6. Examples

Examples 1-12 below give representative experimental procedures for thesyntheses of intermediates useful for the synthesis of compounds offormula (I). Examples 13-18 give representative experimental proceduresfor completion of the syntheses of compounds of formula (I). Example 19reports the biological activity of compounds of formula (I).

All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer.¹H chemical shifts are reported in 6 values in ppm downfield with thedeuterated solvent as the internal standard. Data are reported asfollows: chemical shift, multiplicity (s=singlet, bs=broad singlet,d=doublet, t=triplet, q=quartet, dd=doublet of doublets, m=multiplet,ABq=AB quartet), coupling constant, integration. Reversed-phase LCMSanalysis was performed using an Agilent 1200 system comprised of abinary pump with degasser, high-performance autosampler, thermostattedcolumn compartment, C18 column, diode-array detector (DAD) and anAgilent 6150 MSD with the following parameters. The gradient conditionswere 5% to 95% acetonitrile with the aqueous phase 0.1% TFA in waterover 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEHC18 column (1.7 μm, 1.0×50 mm) at 0.5 mL/min, with column and solventtemperatures maintained at 55° C. The DAD was set to scan from 190 to300 nm, and the signals used were 220 nm and 254 nm (both with a bandwidth of 4 nm). The MS detector was configured with an electrosprayionization source, and the low-resolution mass spectra were acquired byscanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13cycles/second, and peak width of 0.008 minutes. The drying gas flow wasset to 13 liters per minute at 300° C. and the nebulizer pressure wasset to 30 psi. The capillary needle voltage was set at 3000 V, and thefragmentor voltage was set at 100V. Data acquisition was performed withAgilent Chemstation and Analytical Studio Reviewer software.

Example 1 Ethyl6-bromo-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (D)

Ethyl 3-(5-bromo-2-fluorophenyl)-3-oxopropanoate (C)

3-Ethoxy-3-oxopropanoic acid (B) (2.16 mL, 18.3 mmol, 2.00 eq) wasdissolved in THF (91 mL) in an oven dried round-bottom flask and2,2′-bipyridyl (8.00 mg, 0.0512 mmol, 0.0056 eq) was added as anindicator. The reaction was cooled to −30° C. and n-butyllithium (1.6 Min hexanes) (29.0 mL, 45.6 mmol, 4.00 eq) was added dropwise over 20minutes. Upon final addition the reaction turned red at which point itwas allowed to warm to −5° C. The reaction was allowed to stir at −5° C.for 15 minutes, during which time the red color began to dissipate.Enough n-butyllithium was added to cause the red color to persist. Thereaction was then cooled to −78° C. and 5-bromo-2-fluoro-benzoylchloride (A) (2.17 g, 9.14 mmol, 1.00 eq) was added dropwise as asolution in THF (6.9 mL). The reaction was allowed to stir at −78° C.for 30 minutes and then allowed to warm to −30° C. and stirred for anadditional 30 minutes. The reaction was poured onto ice-cold 1N HCl (92mL) and the mixture was extracted with ethyl acetate (lx) and DCM (2×).The combined organics were dried (MgSO₄), filtered and concentrated invacuo. Purification by flash chromatography on silica gel using 0-10%hexanes/ethyl acetate afforded 1.78 g (67%) of the title compound as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (dd, J=6.5, 2.6 Hz,1H), 7.91-7.86 (m, 1H), 7.40-7.34 (m, 1H), 4.13-4.07 (m, 4H), 1.15 (t,J=7.1 Hz, 3H); ES-MS [M+1]⁺: 289.0.

Ethyl6-bromo-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (D)

Compound C (2.87 g, 9.93 mmol, 1.00 eq) and N,N-dimethylformamidedimethyl acetal (1.87 mL, 14.9 mmol, 1.50 eq) were dissolved in DMF (33mL) in a microwave vial and heated in a microwave reactor at 120° C. for15 minutes. To this mixture was then added 4-fluoroaniline (1.41 mL,14.9 mmol, 1.50 eq) and the reaction was heated in a microwave reactorat 150° C. for 20 minutes. The reaction mixture was diluted with ethylacetate and washed with water (2×). The aqueous layers wereback-extracted with ethyl acetate and the combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Purification by flashchromatography on silica gel using 0-45% hexanes/ethyl acetate afforded3.79 g (98%) of the title compound as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.47 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.81 (dd, J=9.1, 2.4Hz, 1H), 7.77-7.73 (m, 2H), 7.54-7.50 (m, 2H), 6.92 (d, J=9.0 Hz, 1H),4.20 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); ES-MS [M+1]⁺: 390.2.

Example 26-Bromo-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (E)

6-Bromo-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (E)

Compound D (1.00 g, 2.56 mmol, 1.00 eq) was suspended in 7N ammonia inmethanol (30 mL) in a microwave vial and the reaction was heated in amicrowave reactor at 150° C. for 60 minutes. The reaction wasconcentrated to afford 881 mg (95%) of the title compound as a brownsolid that was used without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 9.08 (d, J=4.0 Hz, 1H), 8.57 (s, 1H), 8.43 (d, J=2.4 Hz, 1H),7.85 (dd, J=9.1, 2.4 Hz, 1H), 7.77-7.73 (m, 2H), 7.66 (d, J=4.1 Hz, 1H),7.56-7.50 (m, 2H), 7.02 (d, J=9.1 Hz, 1H); ES-MS [M+1]⁺: 361.2.

Example 31-(4-Fluorophenyl)-6-formyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (G)

1-(4-Fluorophenyl)-4-oxo-6-vinyl-1,4-dihydroquinoline-3-carboxamide (F)

To a solution of compound E (450 mg, 1.25 mmol), triethylamine (174 μL,1.25 mmol), and Pd(dppf)Cl₂ CH₂Cl₂ (18.2 mg, 0.025 mmol) in 1-propanol(8.3 mL) was added potassium vinyltrifluoroborate (200 mg, 1.50 mmol).The reaction was purged with argon and stirred at 100° C. for 16 hours.The reaction was filtered over Celite® and washed very well with a 5%MeOH in DCM solution and concentrated in vacuo to give 385 mg (100%) ofthe title compound that was used without further purification. ES-MS[M+1]⁺: 309.2.

1-(4-Fluorophenyl)-6-formyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (G)

To a solution of compound F (385 mg, 1.25 mmol) in 3:1 acetone/water (8mL) was added N-oxide-4-methylmorpholine (220 mg, 1.87 mmol) and osmiumtetroxide (254 μL, 0.025 mmol). After the reaction stirred for one hour,sodium periodate (294 mg, 1.37 mmol) was added. After another two hours,the reaction was diluted with EtOAc and washed well with a 10% NaS₂O₃solution. The organic layer was dried (MgSO4), filtered and concentratedin vacuo to give 365 mg (94%) of the title compound that was usedwithout further purification. ES-MS [M+1]⁺: 311.2.

Example 4 Ethyl1-(4-fluorophenyl)-6-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(I)

Ethyl1-(4-fluorophenyl)-6-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(I)

Ethyl1-(4-fluorophenyl)-6-formyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (H)was prepared from compound D via a method analogous to that described inExample 3. After stirring for two hours, a solution of compound H (10mg, 0.030 mmol), morpholine (3.1 μL, 0.035 mmol), and acetic acid (4.2μL, 0.074 mmol) in dichloromethane (1 mL) was treated with sodiumtriacetoxyborohydride (9.4 mg, 0.044 mmol). After stirring 16 hours, thereaction was concentrated to dryness to give 12 mg (99%) of the titlecompound that was used without further purification. ES-MS [M+1]⁺:411.3.

Example 5 Ethyl1-(4-fluorophenyl)-6-(hydroxymethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(J)

Ethyl1-(4-fluorophenyl)-6-(hydroxymethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(J):

To compound H (335 mg, 0.99 mmol) in ethanol (5 mL) cooled to 0° C. wasadded sodium borohydride (18.7 mg, 0.49 mmol). After ten minutes, thereaction was diluted with EtOAc and washed well with water. The organiclayer was dried (MgSO₄), filtered and concentrated in vacuo.Purification by flash chromatography on silica gel afforded 192 mg (57%)of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 8.25(s, 1H), 7.76-7.72 (m, 2H), 7.61 (d, J=6 Hz, 1H), 7.54 (t, J=8.64, 8.68Hz, 2H), 6.94 (d, J=8.68, 1H), 5.42 (t, J=5.68, 5.64 Hz, 1H), 4.62 (d,J=5.48 Hz, 2H), 4.23 (q, J=7.08 Hz, 2H), 1.27 (t, J=7.12, 7.04 Hz, 3H);ES-MS [M+1]⁺: 342.3.

Example 6 Methyl1-(4-fluorophenyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylate(L)

1-(4-Fluorophenyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (K)

Compound D (500 mg, 1.28 mmol, 1.00 eq), potassium hydroxide (216 mg,3.84 mmol, 3.00 eq), tris(dibenzylideneacetone)dipalladium(0) (70.4 mg,0.0769 mmol, 0.0600 eq) and2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (65.3 mg, 0.154mmol, 0.120 eq) were suspended in a mixture of 1,4-dioxane (3.2 mL) andwater (3.2 mL) in a microwave vial and heated in a microwave reactor at150° C. for 15 minutes. The reaction was neutralized with 2N HCl and themixture was diluted with ethyl acetate and washed with water. Theorganic phase was dried (MgSO4), filtered and concentrated in vacuo toafford 383 mg (99%) of the title compound as a brown solid that was usedwithout further purification. ¹H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H),7.75-7.72 (m, 2H), 7.67 (d, J=2.7 Hz, 1H), 7.51 (t, J=8.7 Hz, 2H), 7.26(d, J=9.1 Hz, 1H), 6.99 (d, J=9.2 Hz, 1H); ES-MS [M+1]⁺: 300.2.

Methyl1-(4-fluorophenyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylate(L)

Compound K (383 mg, 1.28 mmol, 1.00 eq) was dissolved in methanol (6.4mL) and concentrated sulfuric acid (0.64 mL) was added dropwise. Thereaction was heated to reflux for 3 hours at which point it was cooledand neutralized with a saturated solution of sodium bicarbonate. Themixture was extracted with a solution of 3:1 CHCl₃:IPA (2×) and thecombined organics were dried (MgSO₄), filtered and concentrated invacuo. Purification by flash chromatography on silica gel using 0-20%89:10:1 DCM:methanol:NH₄₀H afforded 296 mg (74%) of the title compoundas yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.36 (s,1H), 7.72-7.68 (m, 2H), 7.61 (d, J=2.8 Hz, 1H), 7.49 (t, J=8.7 Hz, 2H),7.11 (dd, J=9.0, 2.8 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 3.71 (s, 3H);ES-MS [M+1]⁺: 314.2.

Example 7 Methyl1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-ylmethoxy)-1,4-dihydroquinoline-3-carboxylate(M)

Methyl1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-ylmethoxy)-1,4-dihydroquinoline-3-carboxylate(M)

Compound L (15 mg, 0.048 mmol, 1.0 eq) and 3-pyridinemethanol (10 mg,0.096 mmol, 2.0 eq) were dissolved in THF (0.5 mL) and cooled to 0° C.Triphenylphosphine (28 mg, 0.11 mmol, 2.2 eq) anddi-tert-butylazodicarboxylate (18 mg, 0.077 mmol, 1.6 eq) were added andthe reaction was stirred at room temperature until complete by LCMS. Thereaction was concentrated and purified using reverse phasechromatography to afford 15 mg (77%) of the title compound as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (d, J=1.7 Hz, 1H), 8.54 (dd,J=4.7, 1.3 Hz, 1H), 8.41 (s, 1H), 7.90-7.88 (m, 1H), 7.79 (d, J=3.0 Hz,1H), 7.73-7.70 (m, 2H), 7.50 (t, J=8.8 Hz, 2H), 7.43 (dd, J=7.8, 4.8 Hz,1H), 7.37 (dd, J=9.3, 3.0 Hz, 1H) 6.94 (d, J=9.2 Hz, 1H), 5.28 (s, 2H),3.72 (s, 3H); ES-MS [M+1]⁺: 405.2.

Example 8 Ethyl1-(4-fluorophenyl)-6-(((2-methylpyrimidin-5-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(N)

Ethyl1-(4-fluorophenyl)-6-(((2-methylpyrimidin-5-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(N)

To a solution of compound J (16 mg, 0.047 mmol) and5-hydroxy-2-methylpyrimidine (6.2 mg, 0.056 mmol) in THF (1 mL) cooledto 0° C. was added triphenylphosphine (27.1 mg, 0.10 mmol) anddi-tert-butylazodicarboxylate (17.3 mg, 0.075 mmol). The reaction wasconcentrated to dryness after 16 hours of stirring. Purification byreverse phase HPLC afforded 20 mg (98%) of the title compound. ES-MS[M+1]⁺: 434.3.

Example 9 Ethyl1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylate(O)

Ethyl1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylate(O)

Compound D (75 mg, 0.19 mmol, 1.0 eq), N-methyl-N-(3-pyridylmethyl)amine(47 mg, 0.38 mmol, 2.0 eq), cesium carbonate (88 mg, 0.27 mmol, 1.4 eq),tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol, 0.080 eq)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg, 0.023 mmol,0.12 eq) were dissolved in toluene (1.9 mL) in a sealed vial and heatedat 110° C. overnight. The reaction was cooled, filtered over Celite® andwashed with 5% methanol in DCM. The organics were concentrated andpurified using reverse phase chromatography to afford 27 mg (33%) of thetitle compound as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s,2H), 8.28 (s, 1H), 7.68 (dd, J=6.9, 4.9 Hz, 2H), 7.58 (d, J=7.8 Hz, 1H),7.47 (t, J=8.7 Hz, 2H), 7.40 (d, J=3.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.21(dd, J=9.3, 3.0 Hz, 1H), 6.80 (d, J=9.3 Hz, 1H), 4.70 (s, 2H), 4.17 (q,J=7.1 Hz, 2H), 3.12 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); ES-MS [M+1]⁺:432.3.

Example 10 Ethyl1-(4-fluorophenyl)-6-((2-methylpyrimidin-5-yl)ethynyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(P)

Ethyl1-(4-fluorophenyl)-6-((2-methylpyrimidin-5-yl)ethynyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(P)

Compound D (50 mg, 0.13 mmol, 1.0 eq), 5-ethynyl-2-methyl-pyrimidine (30mg, 0.26 mmol, 2.0 eq), copper(I) iodide (2.5 mg, 0.013 mmol, 0.010 eq),bis(triphenylphosphine)palladium(II) dichloride (4.5 mg, 0.0064 mmol,0.050 eq) and triethylamine (53.6 μL, 0.38 mmol, 3.0 eq) were dissolvedin DMF (1.3 mL) in a microwave vial and heated in a microwave reactor at150° C. for 15 minutes. The reaction was purified directly using reversephase chromatography to afford 30 mg (55%) of the title compound aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 2H), 8.47 (s, 1H),8.40 (d, J=2.0 Hz, 1H), 7.81-7.76 (m, 3H), 7.53 (t, J=8.7 Hz, 2H), 7.02(d, J=8.80 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.66 (s, 3H), 1.25 (t, J=7.1Hz, 3H); ES-MS [M+1]⁺: 428.2.

Example 11 Ethyl1-(4-fluorophenyl)-4-oxo-6-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-1,4-dihydroquinoline-3-carboxylate(S)

Ethyl1-(4-fluorophenyl)-4-oxo-6-((trimethylsilyl)ethynyl)-1,4-dihydroquinoline-3-carboxylate(Q)

Compound D (450 mg, 1.15 mmol), trimethylsilylacetylene (179 μL, 1.27mmol), PdCl₂(PPh₃)₂ (40.5 mg, 0.058 mmol), CuI (22 mg, 0.12 mmol),triethylamine (321 μL, 2.31 mmol) and DMF (5.8 mL) were added to amicrowave vial. The vial was capped and place in a microwave reactor at150° C. for one hour. The reaction was washed with water and brine andextracted with EtOAc (2×). The organics were combined, dried (MgSO₄),and concentrated to dryness. Purification by flash chromatography onsilica gel afforded 205 mg (44%) of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 8.45 (s, 1H), 8.24 (d, J=1.84 Hz, 1H), 7.76-7.73 (m, 2H),7.68 (dd, J=8.8 Hz, 1H), 7.52 (t, J=8.64, 8.72 Hz, 2H), 6.93 (d, J=8.8Hz, 1H), 4.22 (q, J=7.08 Hz, 2H), 1.25 (t, J=7.12, 7.04 Hz, 3H), 0.24(s, 9H); ES-MS [M+1]⁺: 408.2.

Ethyl6-ethynyl-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(R)

To a solution of Compound Q (205 mg, 0.5 mmol) in THF (2.5 mL) was addeda 1M solution of TBAF in THF (554 μL, 0.55 mmol). After thirty minutesthe reaction was concentrated in vacuo. Purification by flashchromatography on silica gel afforded 110 mg (65%) of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.28 (d, J=1.84 Hz,1H), 7.77-7.69 (m, 3H), 7.54-7.5 (m, 2H), 6.67 (d, J=8.8 Hz, 1H),4.22-4.19 (m, 3H), 1.28-1.23 (m, 3H); ES-MS [M+1]⁺: 336.3.

Ethyl1-(4-fluorophenyl)-4-oxo-6-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-1,4-dihydroquinoline-3-carboxylate(S)

Compound R (20 mg, 0.06 mmol), 4-bromo-2-(trifluoromethyl)pyridine (16.2mg, 0.07 mmol), CuI (1.1 mg, 0.006 mmol), triethylamine (25 μL, 0.18mmol), PdCl₂(PPh₃)₂ (2.7 mg, 0.003 mmol), and DMF (600 μL) were added toa small microwave vial. The vial was capped and placed in microwavereactor at 150° C. for fifteen minutes. The reaction was filtered overCelite®, washed very well with a 5% MeOH in DCM solution andconcentrated to dryness. Purification by reverse phase HPLC afforded 13mg (45%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (d,J=4.96 Hz, 1H), 8.52-8.5 (m, 2H), 8.17 (s, 1H), 7.93 (d, J=5.04 Hz, 1H),7.87 (dd, J=8.8 Hz, 1H), 7.81-7.77 (m, 2H), 7.55 (t, J=8.64, 8.68 Hz,2H), 7.07 (d, J=8.8 Hz, 1H), 4.24 (q, J=7.04, 7.08 Hz, 2H), 1.28 (t,J=7.12, 7.08 Hz, 3H); ES-MS [M+1]⁺: 481.2.

Example 12 Ethyl1-(4-fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(T)

Ethyl1-(4-fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(T)

Compound P (25 mg, 0.059 mmol, 1.0 eq) was dissolved in methanol (2 mL)and palladium on carbon (1 mg) was added. The reaction was pumped andpurged with hydrogen and allowed to stir overnight. The reaction wasfiltered over Celite® and washed with 5% methanol in DCM. The organicswere concentrated and purified using reverse phase chromatography toafford 16 mg (63%) of title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.54 (s, 2H), 8.41 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.74-7.71(m, 2H), 7.55 (dd, J=8.7, 2.1 Hz, 1H), 7.50 (t, J=8.8 Hz, 2H), 6.89 (d,J=8.7 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.04 (t, J=8.3 Hz, 2H), 2.89 (t,J=8.3 Hz, 2H), 2.53 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); ES-MS [M+1]⁺:432.3.

Example 131-(4-Fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(1)

1-(4-Fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(1)

Compound T (11 mg, 0.026 mmol, 1.0 eq) was dissolved in 7N ammonia inmethanol (1 mL) in a microwave vial and heated in a microwave reactor at150° C. for 60 minutes. The reaction was concentrated and purified byreverse phase chromatography to afford 6.7 mg (65%) of the titlecompound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (d, J=4.4Hz, 1H), 8.55 (s, 2H), 8.53 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.76-7.71(m, 2H), 7.62-7.58 (m, 2H), 7.51 (t, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz,1H), 3.06 (t, J=8.3 Hz, 2H), 2.90 (t, J=8.3 Hz, 2H), 2.53 (s, 3H); ES-MS[M+1]⁺: 403.2.

The following compounds were prepared in an analogous manner by firstpreparing the appropriate synthetic intermediate by use of the syntheticprocedures indicated next to each compound:

Examples used to prepare intermediate ES-MS No. Name compound [H + 1]⁺ 21-(4-fluorophenyl)-4-oxo-6- 1, 3, 4 398.4 (thiomorpholinomethyl)-1,4-dihydroquinoline-3-carboxamide 3 1-(4-fluorophenyl)-6- 1, 3, 4 382.2(morpholinomethyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 41-(4-fluorophenyl)-4-oxo-6- 1, 3, 4 380.4 (piperidin-1-ylmethyl)-1,4-dihydroquinoline-3-carboxamide 5 1-(4-fluorophenyl)-4-oxo-6- 1, 10, 12387.2 phenethyl-1,4-dihydroquinoline-3- carboxamide 61-(4-fluorophenyl)-6-(4- 1, 10, 12 401.2 methylphenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide 7 1-(4-fluorophenyl)-6-(3- 1, 10, 12401.3 methylphenethyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 81-(4-fluorophenyl)-6-(2- 1, 10, 12 401.3 methylphenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide 9 1-(4-fluorophenyl)-4-oxo-6-(2- 1, 10,12 388.2 (pyridin-4-yl)ethyl)-1,4- dihydroquinoline-3-carboxamide 101-(4-fluorophenyl)-4-oxo-6-(2- 1, 10, 12 388.2 (pyridin-3-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide 11 1-(4-fluorophenyl)-4-oxo-6-(2- 1, 10,12 388.3 (pyridin-2-yl)ethyl)-1,4- dihydroquinoline-3-carboxamide 121-(4-fluorophenyl)-6- 1, 9 403.2 (methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3- carboxamide 131-(2-fluoro-4-methoxyphenyl)-6-(2- 1, 10, 12 433.3(2-methylpyrimidin-5-yl)ethyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide 14 1-(3-fluoro-4-methoxyphenyl)-6-(2- 1, 10, 12 433.2(2-methylpyrimidin-5-yl)ethyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide 15 1-(4-methoxyphenyl)-6-(2-(2- 1, 10, 12 415.2methylpyrimidin-5-yl)ethyl)-4-oxo- 1,4-dihydroquinoline-3- carboxamide16 1-(4-fluorophenyl)-4-oxo-6- 1, 9 375.2 (pyridin-3-ylamino)-1,4-dihydroquinoline-3-carboxamide 17 1-(4-fluorophenyl)-4-oxo-6- 1, 9 389.3((pyridin-3-ylmethyl)amino)-1,4- dihydroquinoline-3-carboxamide 181-(4-fluorophenyl)-6- 1, 9 389.2 (methyl(pyridin-4-yl)amino)-4-oxo-1,4-dihydroquinoline-3- carboxamide 19 1-(4-fluorophenyl)-6- 1, 9 403.2(methyl(pyridin-4-ylmethyl)amino)- 4-oxo-1,4-dihydroquinoline-3-carboxamide 20 1-(4-fluorophenyl)-6- 1, 9 389.2(methyl(pyridin-3-yl)amino)-4-oxo- 1,4-dihydroquinoline-3- carboxamide21 1-(4-fluorophenyl)-6-((6- 1, 6, 7 404.2methylpyridin-3-yl)methoxy)-4-oxo- 1,4-dihydroquinoline-3- carboxamide22 1-(3-methylisothiazol-5-yl)-6-(2-(2- 1, 10, 12 406.2methylpyrimidin-5-yl)ethyl)-4-oxo- 1,4-dihydroquinoline-3- carboxamide23 1-(4-fluorophenyl)-4-oxo-6-(1- 1, 6, 7 404.2(pyridin-4-yl)ethoxy)-1,4- dihydroquinoline-3-carboxamide 241-(4-fluorophenyl)-6-((2- 1, 6, 7 404.3methylpyridin-4-yl)methoxy)-4-oxo- 1,4-dihydroquinoline-3- carboxamide25 1-(4-fluorophenyl)-4-oxo-6- 1, 6, 7 390.2 (pyridin-4-ylmethoxy)-1,4-dihydroquinoline-3-carboxamide 26 1-(4-fluorophenyl)-4-oxo-6-((2- 1, 9403.2 (pyridin-4-yl)ethyl)amino)-1,4- dihydroquinoline-3-carboxamide 271-(4-fluorophenyl)-4-oxo-6-((2- 1, 9 403.2(pyridin-3-yl)ethyl)amino)-1,4- dihydroquinoline-3-carboxamide 281-(4-fluorophenyl)-6-((2- 1, 9 411.2 morpholinoethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide 29 1-(4-fluorophenyl)-6-((2- 1, 6, 7405.2 methylpyrimidin-5-yl)methoxy)-4- oxo-1,4-dihydroquinoline-3-carboxamide 30 1-(4-fluorophenyl)-4-oxo-6-(1- 1, 6, 7 404.2(pyridin-3-yl)ethoxy)-1,4- dihydroquinoline-3-carboxamide 311-(4-fluorophenyl)-6-(methyl((2- 1, 9 418.2 methylpyrimidin-5-yl)methyl)amino)-4-oxo-1,4- dihydroquinoline-3-carboxamide 321-(4-fluorophenyl)-6-(((3- 1, 3, 5, 8 408.3fluoropyridin-4-yl)oxy)methyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide 33 1-(4-fluorophenyl)-6-(((2- 1, 3, 5, 8 404.3methylpyridin-4-yl)oxy)methyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide 34 1-(4-fluorophenyl)-4-oxo-6-(((2- 1, 3, 5, 8 458.2(trifluoromethyl)pyridin-4- yl)oxy)methyl)-1,4-dihydroquinoline-3-carboxamide 35 1-(4-fluorophenyl)-6-(((2- 1, 3, 5, 8405.4 methylpyrimidin-5-yl)oxy)methyl)- 4-oxo-1,4-dihydroquinoline-3-carboxamide 36 1-(4-fluorophenyl)-4-oxo-6-(((6- 1, 3, 5, 8 458.2(trifluoromethyl)pyridin-3- yl)oxy)methyl)-1,4-dihydroquinoline-3-carboxamide 37 6-(((6-chloropyridin-3- 1, 3, 5, 8424.2 yl)oxy)methyl)-1-(4-fluorophenyl)- 4-oxo-1,4-dihydroquinoline-3-carboxamide 38 1-(4-fluorophenyl)-4-oxo-6-(2- 1, 9 443.2(pyridin-3-yl)piperidin-1-yl)-1,4- dihydroquinoline-3-carboxamide 391-(4-fluorophenyl)-6-(((2- 1, 3, 5, 8 408.3fluoropyridin-3-yl)oxy)methyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide 40 1-(4-fluorophenyl)-4-oxo-6-(2- 1, 9 429.2(pyridin-3-yl)pyrrolidin-1-yl)-1,4- dihydroquinoline-3-carboxamide 411-(4-fluorophenyl)-6-(((6- 1, 3, 5, 8 404.3methylpyridin-3-yl)oxy)methyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide 42 6-(ethyl(pyridin-3-ylmethyl)amino)- 1, 9 417.21-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 431-(4-fluorophenyl)-4-oxo-6-(5H- 1, 9 401.2pyrrolo[3,4-b]pyridin-6(7H)-yl)-1,4- dihydroquinoline-3-carboxamide 441-(4-fluorophenyl)-4-oxo-6- 1, 6, 7 390.2 (pyridin-3-ylmethoxy)-1,4-dihydroquinoline-3-carboxamide 45 1-(4-fluorophenyl)-6-(((6- 1, 3, 5, 8408.3 fluoropyridin-3-yl)oxy)methyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide 46 1-(4-fluorophenyl)-4-oxo-6-(2-(2- 1, 11, 12 456.4(trifluoromethyl)pyridin-4-yl)ethyl)- 1,4-dihydroquinoline-3-carboxamide 47 1-(4-fluorophenyl)-4-oxo-6-(2-(6- 1, 11, 12 456.2(trifluoromethyl)pyridin-3-yl)ethyl)- 1,4-dihydroquinoline-3-carboxamide 48 1-(4-fluorophenyl)-6-(2-(5- 1, 11, 12 406.4fluoropyridin-3-yl)ethyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 498-fluoro-1-(4-fluorophenyl)-6-(2-(2- 1, 10, 12 421.2methylpyrimidin-5-yl)ethyl)-4-oxo- 1,4-dihydroquinoline-3- carboxamide50 1-(4-fluorophenyl)-6-(3- 1, 9 437.2 morpholinopyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxamide 51 8-fluoro-1-(4-fluorophenyl)-6- 1,9 421.2 (methyl(pyridin-3-ylmethyl)amino)- 4-oxo-1,4-dihydroquinoline-3-carboxamide

Example 147-Fluoro-1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide(52)

7-Fluoro-1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (V)

Ethyl7-fluoro-1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylate(U) was prepared from 5-bromo-2,4-difluorobenzoyl chloride via a methodanalogous to that described in Examples 1 and 9. Compound U (27 mg,0.060 mmol, 1.0 eq) was dissolved in 1,4-dioxane (0.5 mL) and 1N sodiumhydroxide (0.12 mL, 0.12 mmol, 2.0 eq) was added. The reaction wasstirred until complete by LCMS, at which time it was neutralized to pH4-5 with 1N HCl and concentrated to dryness. The residue was suspendedin 10% methanol in DCM and filtered. The organics were concentrated toafford 25 mg (99%) of the title compound as an off-white solid that wasused without further purification. ES-MS [M+1]⁺: 422.2.

7-Fluoro-1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide(52)

Compound U (26 mg, 0.062 mmol, 1.0 eq), ammonium chloride (6.6 mg, 0.12mmol, 2.0 eq),(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (28 mg, 0.074 mmol, 1.2 eq) andN,N-diisopropylethylamine (43 μL, 0.25 mmol, 4.0 eq) were dissolved inDMF (0.5 mL) and stirred overnight. The reaction was diluted with ethylacetate and washed with water (2×). The aqueous phase was back extractedwith ethyl acetate and the combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Purification by reverse phasechromatography afforded 7.0 mg (27%) of the title compound as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (d, J=4.4 Hz, 1H), 8.48-8.45 (m,3H), 7.76-7.72 (m, 3H), 7.67 (dt, J=7.8, 1.7 Hz, 1H), 7.58 (d, J=4.4 Hz,1H), 7.51 (t, J=8.7 Hz, 2H), 7.35 (dd, J=7.7, 4.9 Hz, 1H), 6.81 (d,J=14.0 Hz, 1H), 4.41 (s, 2H), 2.83 (s, 3H); ES-MS [M+1]⁺: 421.2.

The following compounds were prepared in an analogous manner by firstpreparing the appropriate synthetic intermediate by use of the syntheticprocedures indicated next to each compound:

Examples used to prepare intermediate ES-MS No. Name compound [M + 1]⁺53 1-(4-fluorophenyl)-4-oxo-6- 1, 9 396.2 (((tetrahydro-2H-pyran-4-yl)methyl)amino)-1,4- dihydroquinoline-3-carboxamide 547-fluoro-1-(4-fluorophenyl)-6-(2- 1, 10, 12 421.2(2-methylpyrimidin-5-yl)ethyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide

Example 151-(4-Fluorophenyl)-6-((6-methylpyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide(55)

1-(4-Fluorophenyl)-6-((6-methylpyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide(55)

Compound E (15 mg, 0.042 mmol, 1.0 eq), 5-hydroxy-2-methylpyridine (9.1mg, 0.083 mmol, 2.0 eq), cesium carbonate (27 mg, 0.083 mmol, 2.0 eq),copper(I) iodide (0.79 mg, 0.0042 mmol, 0.10 eq) and N,N-dimethylglycine(1.3 mg, 0.013 mmol, 0.30 eq) were dissolved in DMF in a microwave vialand heated in a microwave reactor at 150° C. for 15 minutes. Thereaction was filtered over Celite® and washed with 5% methanol in DCM.The organics were concentrated and purified using reverse phasechromatography to afford 9.1 mg (56%) of title compound as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (d, J=4.3 Hz, 1H), 8.54 (s, 1H),8.33 (d, J=2.8 Hz, 1H), 7.77-7.73 (m, 2H), 7.68 (d, J=3.0 Hz, 1H), 7.59(d, J=4.3 Hz, 1H), 7.56-7.47 (m, 4H), 7.34 (d, J=8.5 Hz, 1H), 7.12 (d,J=9.2 Hz, 1H), 2.49 (s, 3H); ES-MS [M+1]⁺: 390.4.

The following compounds were prepared in an analogous manner by firstpreparing the appropriate synthetic intermediate by use of the syntheticprocedures indicated next to each compound:

Examples used to prepare intermediate ES-MS No. Name compound [M + 1]⁺56 1-(4-fluorophenyl)-4-oxo-6- 1, 2 376.2 (pyridin-3-yloxy)-1,4-dihydroquinoline-3-carboxamide 57 1-(4-fluorophenyl)-6-((2- 1, 2 391.3methylpyrimidin-5-yl)oxy)-4-oxo- 1,4-dihydroquinoline-3- carboxamide 581-(4-fluorophenyl)-6-((6- 1, 2 394.3 fluoropyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide 59 1-(4-fluorophenyl)-6-((5- 1, 2 394.2fluoropyridin-3-yl)oxy)-4-oxo-1,4- dihydroquinoline-3-carboxamide

Example 161-(4-fluorophenyl)-4-oxo-6-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxamide(60)

1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxamide(60)

Compound E (15 mg, 0.042 mmol, 1.0 eq), 3-pyridinylboronic acid (11 mg,0.087 mmol, 2.1 eq),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.0 mg,0.0042 mmol, 0.10 eq) and 1N sodium carbonate (0.21 mL, 0.21 mmol, 5.0eq) were dissolved in dimethoxyethane (0.6 mL) in a microwave vial andheated at 150° C. for 20 minutes in a microwave reactor. The reactionwas portioned between ethyl acetate and water and the layers separated.The aqueous phase was extracted with an additional portion of ethylacetate and the combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Purification by reverse phase chromatographyafforded 10.1 mg (68%) of the title compound as white solid. ¹H NMR (400MHz, DMSO-d₆) δ 9.21 (d, J=4.3 Hz, 1H), 8.96 (d, J=1.9 Hz, 1H), 8.62 (m,2H), 8.60 (s, 1H), 8.17 (dt, J=8.0, 1.7 Hz, 1H), 8.09 (dd, J=8.8, 2.3Hz, 1H), 7.81-7.78 (m, 2H), 7.66 (d, J=4.3 Hz, 1H), 7.57-7.52 (m, 3H),7.16 (d, J=8.8 Hz, 1H); ES-MS [M+1]⁺: 360.2.

The following compounds were prepared in an analogous manner by firstpreparing the appropriate synthetic intermediate by use of the syntheticprocedures indicated next to each compound:

Examples used to prepare intermediate ES-MS No. Name compound [M + 1]⁺61 1-(4-fluorophenyl)-6-(1-methyl- 1, 2 363.21H-pyrazol-4-yl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 621-(4-fluorophenyl)-6-(2- 1, 2 375.2 methylpyrimidin-5-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide 63 1-(4-fluorophenyl)-4-oxo-6- 1, 2 360.2(pyridin-4-yl)-1,4- dihydroquinoline-3-carboxamide

Example 176-((cis-2,6-Dimethylmorpholino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(64)

6-((cis-2,6-dimethylmorpholino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(64)

A solution of compound G (10 mg, 0.032 mmol), cis-2,6-dimethylmorpholine(5 μL, 0.039 mmol), and acetic acid (4.6 μL, 0.081 mmol) indichloromethane (1 mL) were stirred for one hour. To this mixture wasadded sodium triacetoxyborohydride (10.2 mg, 0.048 mmol). After 16hours, the reaction was concentrated to dryness. Purification by reversephase HPLC afforded 5 mg (38%) of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 9.23 (d, J=4.4 Hz, 1H), 8.55 (s, 1H), 8.26 (d, J=1.8 Hz, 1H),7.77-7.73 (m, 2H), 7.65 (dd, J=8.7, 2 Hz, 1H), 7.59 (d, J=4.4 Hz, 1H),7.52 (t, J=8.68, 8.76, 2H), 7.03 (d, J=8.68, 1H), 3.57-3.52 (m, 4H),2.65 (d, J=10.2 Hz, 2H), 1.01 (d, J=6.3 Hz, 6H); ES-MS [M+1]⁺: 410.3.

The following compounds were prepared in an analogous manner by firstpreparing the appropriate synthetic intermediate by use of the syntheticprocedures indicated next to each compound:

Examples used to prepare intermediate ES-MS No. Name compound [M + 1]⁺65 6-((6,6-difluoro-2-azaspiro[3.3]heptan-2- 1, 2, 3 428.2yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide66 6-((4-cyclopropylpiperazin-1-yl)methyl)-1- 1, 2, 3 421.2(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 671-(4-fluorophenyl)-6-((octahydroquinolin- 1, 2, 3 434.21(2H)-yl)methyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 686-((4,7-dimethyl-1,4-diazepan-1- 1, 2, 3 423.2yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide69 6-((cyclopentyl(methyl)amino)methyl)-1- (4-fluorophenyl)-4-oxo-1,4-1, 2, 3 394.2 dihydroquinoline-3-carboxamide 706-((cyclopropyl(methyl)amino)methyl)-1- 1, 2, 3 366.2(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 716-((1,4-thiazepan-4-yl)methyl)-1-(4- 1, 2, 3 412.2fluorophenyl)-4-oxo-1,4-dihydroquinoline- 3-carboxamide 726-((1,4-oxazepan-4-yl)methyl)-1-(4- 1, 2, 3 396.2fluorophenyl)-4-oxo-1,4-dihydroquinoline- 3-carboxamide 736-(azepan-1-ylmethyl)-1-(4-fluorophenyl)- 1, 2, 3 394.24-oxo-1,4-dihydroquinoline-3-carboxamide 74 1-(4-fluorophenyl)-6-((4- 1,2, 3 410.2 methoxypiperidin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide 756-((4-cyanopiperidin-1-yl)methyl)-1-(4- 1, 2, 3 405.2fluorophenyl)-4-oxo-1,4-dihydroquinoline- 3-carboxamide 761-(4-fluorophenyl)-6-((4- 1, 2, 3 458.2(methylsulfonyl)piperidin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide 771-(4-fluorophenyl)-4-oxo-6-((4- 1, 2, 3 448.2(trifluoromethyl)piperidin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxamide 786-((4,4-difluoropiperidin-1-yl)methyl)-1- 1, 2, 3 416.2(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 791-(4-fluorophenyl)-6-((2- 1, 2, 3 396.2methylmorpholino)methyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 806-(((3,3- 1, 2, 3 416.2 difluorocyclobutyl)(methyl)amino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 811-(4-fluorophenyl)-4-oxo-6-((4-(2,2,2- 1, 2, 3 463.2trifluoroethyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxamide 826-((4-acetylpiperazin-1-yl)methyl)-1-(4- 1, 2, 3 423.2fluorophenyl)-4-oxo-1,4-dihydroquinoline- 3-carboxamide 831-(4-fluorophenyl)-6-((4- 1, 2, 3 459.2(methylsulfonyl)piperazin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide 846-((1,1-dioxidothiomorpholino)methyl)-1- 1, 2, 3 430.2(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 856-((1,1-dioxido-1,4-thiazepan-4- 1, 2, 3 444.2yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide86 6-((3,3-difluoropyrrolidin-1-yl)methyl)-1- 1, 2, 3 402.2(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 871-(4-fluorophenyl)-6-((4-methylpiperazin- 1, 2, 3 395.21-yl)methyl)-4-oxo-1,4-dihydroquinoline- 3-carboxamide 88(S)-1-(4-fluorophenyl)-6-((2- 1, 2, 3 396.4methylmorpholino)methyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 89(R)-1-(4-fluorophenyl)-6-((2- 1, 2, 3 396.4methylmorpholino)methyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 906-((2,2-dimethylmorpholino)methyl)-1-(4- 1, 2, 3 410.4fluorophenyl)-4-oxo-1,4-dihydroquinoline- 3-carboxamide 91 6-(((3,3- 1,2, 3 434.3 difluorocyclobutyl)(methyl)amino)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 926-((cis-2,6-dimethylmorpholino)methyl)-8- 1, 2, 3 428.4fluoro-1-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 938-fluoro-1-(4-fluorophenyl)-6-((2- 1, 2, 3 414.2methylmorpholino)methyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 946-((4,4-difluoropiperidin-1-yl)methyl)-8- 1, 2, 3 434.2fluoro-1-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide 956-((3,3-difluoropyrrolidin-1-yl)methyl)-8- 1, 2, 3 420.2fluoro-1-(4-fluorophenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide

Example 181-(4-Fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carbonitrile(96)

6-bromo-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carbonitrile (W)

Compound E (30 mg, 0.083 mmol, 1.0 eq) and cyanuric chloride (15 mg,0.083 mmol, 1.0 eq) were dissolved in DMF (0.5 mL) and the reaction wasstirred at room temperature for 30 minutes. The reaction was dilutedwith ethyl acetate and washed with saturated sodium bicarbonate. Theorganic phase was dried (MgSO₄), filtered and concentrated in vacuo.Purification by reverse phase chromatography afforded 10.1 mg (68%) ofthe title compound as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (s,1H), 8.30 (d, J=2.4 Hz, 1H), 7.86 (dd, J=9.0, 2.4 Hz, 1H), 7.75-7.72 (m,2H), 7.53 (t, J=8.7 Hz, 2H), 6.96 (d, J=9.1 Hz, 1H); ES-MS [M+1]⁺:343.2.

1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carbonitrile(96)

Compound W (25 mg, 0.073 mmol, 1.0 eq),N-methyl-N-(3-pyridylmethyl)amine (17 mg, 0.15 mmol, 2.0 eq), cesiumcarbonate (33 mg, 0.10 mmol, 1.4 eq),tris(dibenzylideneacetone)dipalladium(0) (5.3 mg, 0.0058 mmol, 0.080 eq)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.1 mg, 0.0087mmol, 0.12 eq) were dissolved in toluene (0.5 mL) in a sealed vial andheated at 110° C. overnight. The reaction was cooled, filtered overCelite® and washed with 5% methanol in DCM. The organics wereconcentrated and purified using reverse phase chromatography to afford11.3 mg (40%) of the title compound as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.65 (s, 1H), 8.44-8.42 (m, 2H), 7.70-7.67 (m, 2H), 7.57 (dt,J=7.8, 1.8 Hz, 1H), 7.48 (t, J=8.7 Hz, 2H), 7.33-7.32 (m, 2H), 7.26 (dd,J=9.4, 3.1 Hz, 1H), 6.83 (d, J=9.3 Hz, 1H), 4.72 (s, 2H), 3.1 (s, 3H);ES-MS [M+1]⁺: 385.2.

Example 19 Biological Activity

A. mGlu₂ Ca²⁺Flux Assay

G_(α15) HEK293 cells stably expressing rat mGlu₂ were plated inblack-walled, clear-bottomed, poly-D-lysine coated 384-well plates in 20μL of assay medium (DMEM containing 10% dialyzed FBS, 20 mM HEPES, and 1mM sodium pyruvate) at a density of 12K cells/well. The cells were grownovernight at 37° C. in the presence of 5% CO₂. The next day, medium wasremoved and the cells incubated with 20 μL of 2.3 μM Fluo-4, AM preparedas a 2.3 mM stock in DMSO and mixed in a 1:1 ratio with 10% (w/v)pluronic acid F-127 and diluted in assay buffer (Hank's balanced saltsolution, 20 mM HEPES, and 2.5 mM probenecid) for 45 minutes at 37° C.Dye was removed, 20 μL of assay buffer was added, and the plate wasincubated for 5 minutes at room temperature.

Ca²⁺ flux was measured using the Functional Drug Screening System(FDSS7000, Hamamatsu, Japan). After establishment of a fluorescencebaseline for about 3 seconds, the compounds of the present inventionwere added to the cells, and the response in cells was measured. 2.3minutes later an EC₂₀ concentration of the mGlu₂ receptor agonistglutamate was added to the cells, and the response of the cells wasmeasured for 1.9 minutes; an EC₈₀ concentration of agonist was added andreadings taken for an additional 1.7 minutes. All test compounds weredissolved and diluted to a concentration of 10 mM in 100% DMSO.Compounds were then serially diluted 1:3 in DMSO into 10 pointconcentration response curves, transferred to daughter plates, andfurther diluted into assay buffer to a 2× stock. Calcium fluorescencemeasures were recorded as fold over basal fluorescence; raw data wasthen normalized to the maximal response to glutamate. Antagonism of theagonist response of the mGlu₂ receptor in the present invention wasobserved as a decrease in response to nearly maximal concentrations ofglutamate in the presence of compound compared to the response toglutamate in the absence of compound.

The raw data file containing all time points was used as the data sourcein the analysis template. This was saved by the FDSS as a tab-delimitedtext file. Data were normalized using a static ratio function (F/F₀) foreach measurement of the total 360 values per well divided by each well'sinitial value. Data were then reduced to peak amplitudes (Max−InitialMin) using a time range that starts approximately 3 seconds prior to theglutamate EC₈₀ addition and continues for approximately 90 seconds. Thisis sufficient time to capture the peak amplitude of the cellular calciumresponse. Individual amplitudes were expressed as % EC_(Max) bymultiplying each amplitude by 100 and then dividing the product by themean of the amplitudes derived from the glutamate EC_(Max)-treatedwells. IC50 values for test compounds were generated by fitting thenormalized values versus the log of the test compound concentration (inmol/L) using a 4 parameter logistic equation where none of theparameters were fixed. Each of the three values collected at eachconcentration of test compound were weighted evenly.

A compound was designated as a negative allosteric modulator (NAM) ifthe compound showed a concentration-dependent decrease in the glutamateEC₈₀ addition. For NAMs, potency (IC₅₀) and maximum response (% GluMax), i.e. the amplitude of response in the presence of 30 μM testcompound as a percentage of the maximal response to glutamate, arereported. For NAMs that show a decrease in the EC₈₀ response, but do nothit a plateau, the average of the maximum response at a singleconcentration (30 μM) was determined (% Glu Max) and potencies werereported as “>10,000 nM”. Compounds with no measurable activity aredesignated as “>30,000 nM” since the top concentration of compoundtested in the assay is 30 μM.

B. Results and Discussion of Biological Activity Data

The results of these assays are shown in Table 1. The data in Table 1demonstrates that the disclosed compounds are negative allostericmodulators of mGlu₂ and show high affinity for the mGlu₂ receptor(s).Data is from a single experiment unless otherwise noted. Data that is anaverage of two experiments is noted as “n=2” while data that is anaverage of three or more experiments is presented as the average plus orminus the standard error of the mean.

TABLE 1 rat mGlu₂ rat mGlu₂ Glu max Compound IC₅₀ (nM) (%) 1 227 ± 55 1.52 ± 0.26 2 440 ± 97  1.52 ± 0.63 3 3910 −0.78 4 >10,000 53.77 510,000 4.65 6 >10,000 68.47 7 >10,000 42.15 8 >10,000 18.67 9 492 ± 97 1.88 ± 0.38 10 482 ± 87  1.90 ± 0.11 11 2590 0.92 12 202 ± 14  2.39 ±0.13 13 311 (n = 2) 1.14 (n = 2) 14 252 (n = 2) 1.15 (n = 2) 15 139 (n =2) 1.61 (n = 2) 16 433 (n = 2) 1.77 (n = 2) 17 421 (n = 2) 1.05 (n = 2)18 1150 1.73 19 224 (n = 2) 1.02 (n = 2) 20 155 (n = 2) 1.33 (n = 2) 21541 ± 116 1.55 ± 0.39 22 419 ± 46  1.20 ± 0.50 23 460 ± 62  1.07 ± 0.1324 422 ± 94  1.09 ± 0.16 25 1230 0.97 26 444 (n = 2) 1.91 (n = 2) 27 391(n = 2) 1.75 (n = 2) 28 1150 0.77 29 843 1.92 30 391 ± 44  1.31 ± 0.4531 153 ± 33  1.86 ± 0.26 32 243 ± 63  1.83 ± 0.20 33 421 (n = 2) 2.18 (n= 2) 34 534 1.97 35 287 ± 51  1.71 ± 0.20 36 1460 1.28 37 203 ± 42  1.70± 0.12 38 900 1.68 39 883 0.83 40 429 1.81 41 265 ± 73  1.62 ± 0.23 42167 2.57 43 5040 1.85 44 1080 1.67 45 352 (n = 2) 1.47 (n = 2) 46 2690.78 47 1550 1.21 48 1030 1.40 49 155 (n = 2) 1.53 (n = 2) 50 1320 1.0851 1180 1.39 52 669 2.26 53 659 1.04 54 2700 1.02 55 1710 1.96 56 882 ±160 1.84 ± 0.47 57 4480 15.71 58 1360 1.18 59 2110 0.44 60 277 1.33 61544 (n = 2) 0.41 (n = 2) 62 >10,000 30.30 63 407 0.97 64 222 ± 36  1.42± 0.51 65 2020 1.93 66 1290 1.89 67 617 2.40 68 4040 2.47 69 2190 1.3970 821 1.33 71 164 (n = 2) 2.06 (n = 2) 72 >10,000 29.60 73 2590 0.96 741880 1.23 75 735 1.02 76 1120 1.29 77 823 1.41 78 197 ± 91  1.59 ± 0.2779 328 ± 64  1.31 ± 0.04 80 397 (n = 2) 1.03 (n = 2) 81 753 1.19 82 31902.14 83 694 1.47 84 1160 2.04 85 422 ± 52  1.24 ± 0.04 86 259 (n = 2)0.98 (n = 2) 87 1360 0.93 88 724 1.36 89 1150 1.08 90 142 (n = 2) 2.01(n = 2) 91 >30,000 N/A 92 4410 2.23 93 6520 0.14 94 1770 5.78 95 >10,00031.09 96 3160 3.44

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents.

Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art. Such changes and modifications,including without limitation those relating to the chemical structures,substituents, derivatives, intermediates, syntheses, compositions,formulations, or methods of use of the invention, may be made withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein R¹ is arylheteroaryl; R^(2a), R^(2b), and R^(2c) are each independently selectedfrom hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, andC₁-C₄ haloalkoxy; R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N(R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A, -A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; p is 0-2; q is 0-2; X, Y, and Z are eachindependently selected from a bond, CR^(8e)R^(8f), O, S, NR¹⁰, —C(O)—,—O—C(O)—, —C(O)—O—, —O—C(O)—NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,—NR¹⁰—C(O)—O—, —NR¹⁰—C(O)—NR—, —NR¹⁰—SO₂—, and —SO₂—; R^(7a) and R^(7b)are each independently selected from C₁-C₇ alkyl, C₁-C₇ haloalkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; A′ is aryl,heteroaryl, cycloalkyl, or heterocycle; and R⁴ is —CONH₂ or cyano;wherein said aryl, heteroaryl, cycloalkyl, and heterocycle, at eachoccurrence, are independently substituted or unsubstituted.
 2. Thecompound of claim 1, wherein R¹ is aryl or heteroaryl, substituted with0-3 substituents independently selected from fluoro, chloro, cyano,C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ alkoxyalkyl, cyclopropyl,fluorocyclopropyl, OR⁵, and NR^(6a)R^(6b); wherein R⁵ is hydrogen, C₁-C₆alkyl or C₁-C₆ fluoroalkyl; and R^(6a) and R^(6b) are each independentlyhydrogen, C₁-C₆ alkyl, cyclopropyl, cyclobutyl, or C₁-C₆ heteroalkyl; orR^(6a) and R^(6b) together with the nitrogen atom to which they areattach form a heterocycle; wherein each R^(6a) and R^(6b) aresubstituted with 0-3 fluorine atoms.
 3. The compound of claim 1, whereinR¹ is aryl substituted with 0-2 substituents independently selected fromfluoro, chloro, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ alkoxyalkyl, andOR⁵; wherein R⁵ is hydrogen, C₁-C₃ alkyl, or C₁-C₃ fluoroalkyl.
 4. Thecompound of claim 1, wherein R¹ is heteroaryl substituted with 0-2substituents independently selected from fluoro, chloro, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxyalkyl.
 5. The compound of claim 1,wherein R^(2a), R^(2b), and R^(2c) are each independently hydrogen,fluoro, or chloro.
 6. The compound of claim 1, wherein R^(2a), R^(2b),and R^(2c) are each hydrogen.
 7. The compound of claim 1, wherein R³ is—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—N((R^(7a))(R^(7b)),—X—(CR^(8a)R^(8b))_(p)—Z—(CR^(8c)R^(8d))_(q)—Y-A, -A′—X—(CR^(8a)R^(8b))_(p)—N(R^(7a))(R^(7b)), or-A′—X—(CR^(8a)R^(8b))_(p)—Y-A; wherein p is 0-2; q is 0-2; X is a bond,CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond, CR^(8e)R^(8f), O, or NR¹⁰;R^(7a) and R^(7b) are each independently selected from C₁-C₇ alkyl,cycloalkyl, C₁-C₇ heteroalkyl, and heterocycle, or R^(7a) and R^(7b)together with the nitrogen atom to which they attach form a heterocycle;R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f), at each occurrence,are independently selected from hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R¹⁰ at each occurrence isindependently selected from hydrogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;A is aryl, heteroaryl, cycloalkyl, or heterocycle; and A′ is cycloalkylor heterocycle.
 8. The compound of claim 1, wherein R³ is

wherein X is a bond, CR^(8e)R^(8f), O, or NR¹⁰; Y is a bond,CR^(8e)R^(8f), O, or NR¹⁰; R^(7a) and R^(7b) are each independentlyselected from C₁-C₇ alkyl, C₃-C₇ cycloalkyl, C₁-C₇ heteroalkyl, andmonocyclic heterocycle, or R^(7a) and R^(7b) together with the nitrogenatom to which they attach form a heterocycle; wherein R^(7a) and R^(7b)are substituted with 0-3 fluorine atoms; R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are each independently selected from hydrogen, fluoro,and methyl; R⁹ at each occurrence is independently selected from fluoro,methyl, heterocycle, and heteroaryl; wherein 0-4 R⁹ groups are presentin each R³; m is 0-3; n is 0-2; R¹⁰ is hydrogen, C₁-C₃ alkyl, or C₁-C₃fluoroalkyl; A is an aryl group of 6-10 atoms, a heteroaryl group of5-10 atoms, C₃-C₇ cycloalkyl, a heterocycle group of 4-10 atoms, or aspiro heterocycle group of 7-10 atoms; wherein A is substituted with 0-3substituents independently selected from fluoro, chloro, cyano, methyl,C₁-C₃ fluoroalkyl, cycloalkyl, OR¹¹, NR^(12a)R^(12b), SO₂R¹¹, and COR¹¹;wherein R¹¹ is independently selected from hydrogen, C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; R^(12a) and R^(12b) are each independently selectedfrom hydrogen, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and C₁-C₄heteroalkyl; or R^(12a) and R^(12b) together with the nitrogen atom towhich they attach form a heterocycle; wherein each R^(12a) and R^(12b)are each independently substituted with 0-3 fluorine atoms.
 9. Thecompound of claim 1, wherein R³ is


10. The compound of claim 1, wherein R⁴ is —CONH₂.
 11. The compound ofclaim 1, wherein R⁴ is cyano.
 12. The compound of claim 1, selected fromthe group consisting of:1-(4-fluorophenyl)-4-oxo-6-(thiomorpholinomethyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(piperidin-1-ylmethyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-phenethyl-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(4-methylphenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(3-methylphenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(2-methylphenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-4-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-3-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-2-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-yloxy)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(2-fluoro-4-methoxyphenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(3-fluoro-4-methoxyphenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-methoxyphenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-ylamino)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-((pyridin-3-ylmethyl)amino)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(methyl(pyridin-4-yl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(methyl(pyridin-4-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((2-methylpyrimidin-5-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((6-fluoropyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((6-methylpyridin-3-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(methyl(pyridin-3-yl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((4-cyclopropylpiperazin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((octahydroquinolin-1(2H)-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((4,7-dimethyl-1,4-diazepan-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((cyclopentyl(methyl)amino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((cyclopropyl(methyl)amino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((1,4-thiazepan-4-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((1,4-oxazepan-4-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-(azepan-1-ylmethyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((4-methoxypiperidin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((4-cyanopiperidin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((4-(methylsulfonyl)piperidin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxamide;6-((4,4-difluoropiperidin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-(((3,3-difluorocyclobutyl)(methyl)amino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((cis-2,6-dimethylmorpholino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxamide;6-((4-acetylpiperazin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((1,1-dioxidothiomorpholino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((1,1-dioxido-1,4-thiazepan-4-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((4-methylpiperazin-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((6-methylpyridin-3-yl)methoxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(3-methylisothiazol-5-yl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(1-(pyridin-4-yl)ethoxy)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((2-methylpyridin-4-yl)methoxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(pyridin-4-ylmethoxy)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-((2-(pyridin-4-yl)ethyl)amino)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-((2-(pyridin-3-yl)ethyl)amino)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((2-morpholinoethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-((2-methylpyrimidin-5-yl)methoxy)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(1-(pyridin-3-yl)ethoxy)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(methyl((2-methylpyrimidin-5-yl)methyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(((3-fluoropyridin-4-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(((2-methylpyridin-4-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(((2-(trifluoromethyl)pyridin-4-yl)oxy)methyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(((2-methylpyrimidin-5-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1,4-dihydroquinoline-3-carboxamide;6-(((6-chloropyridin-3-yl)oxy)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-3-yl)piperidin-1-yl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(((2-fluoropyridin-3-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(2-(pyridin-3-yl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(((6-methylpyridin-3-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-(ethyl(pyridin-3-ylmethyl)amino)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-ylmethoxy)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carbonitrile;1-(4-fluorophenyl)-6-(((6-fluoropyridin-3-yl)oxy)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(2-(2-(trifluoromethyl)pyridin-4-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(2-(5-fluoropyridin-3-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;8-fluoro-1-(4-fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(3-morpholinopyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;8-fluoro-1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-6-(2-methylpyrimidin-5-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(pyridin-4-yl)-1,4-dihydroquinoline-3-carboxamide;1-(4-fluorophenyl)-4-oxo-6-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxamide;(S)-1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;(R)-1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((2,2-dimethylmorpholino)methyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-(((3,3-difluorocyclobutyl)(methyl)amino)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((cis-2,6-dimethylmorpholino)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;8-fluoro-1-(4-fluorophenyl)-6-((2-methylmorpholino)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((4,4-difluoropiperidin-1-yl)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;6-((3,3-difluoropyrrolidin-1-yl)methyl)-8-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;7-fluoro-1-(4-fluorophenyl)-6-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxamide;and7-fluoro-1-(4-fluorophenyl)-6-(2-(2-methylpyrimidin-5-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of claim 1, or a pharmaceutically acceptable salt thereof, incombination with one or more pharmaceutically acceptable carriers.